chr2-240787229-A-G

Variant names:

• chr2-240787229-A-G
• rs2288746
• NM_001244008.2:c.429+22T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.429+22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,601,840 control chromosomes in the GnomAD database, including 147,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19687 hom., cov: 34)
  • Exomes 𝑓: 0.42 (127948 hom.)
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.305
• Publications: 7 publications found

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-240787229-A-G is Benign according to our data. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240787229-A-G is described in CliVar as Benign. Clinvar id is 673387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.429+22T>C		intron_variant	Intron 5 of 48	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.429+22T>C		intron_variant	Intron 5 of 48	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74477 AN: 152008 Hom.: 19646 Cov.: 34

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.446

GnomAD2 exomes AF: 0.413 AC: 102247 AN: 247550 AF XY: 0.402

Gnomad AFR exome AF: 0.709

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.374

Gnomad NFE exome AF: 0.425

Gnomad OTH exome AF: 0.420

GnomAD4 exome AF: 0.415 AC: 602049 AN: 1449714 Hom.: 127948 Cov.: 30 AF XY: 0.410 AC XY: 296123 AN XY: 722016

African (AFR) AF: 0.715 AC: 23729 AN: 33210

American (AMR) AF: 0.395 AC: 17633 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 8879 AN: 26032

East Asian (EAS) AF: 0.468 AC: 18559 AN: 39616

South Asian (SAS) AF: 0.289 AC: 24852 AN: 86008

European-Finnish (FIN) AF: 0.386 AC: 20333 AN: 52676

Middle Eastern (MID) AF: 0.376 AC: 2156 AN: 5734

European-Non Finnish (NFE) AF: 0.418 AC: 460891 AN: 1101774

Other (OTH) AF: 0.417 AC: 25017 AN: 59998

GnomAD4 genome AF: 0.490 AC: 74544 AN: 152126 Hom.: 19687 Cov.: 34 AF XY: 0.482 AC XY: 35832 AN XY: 74370

African (AFR) AF: 0.700 AC: 29065 AN: 41502

American (AMR) AF: 0.435 AC: 6652 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1192 AN: 3470

East Asian (EAS) AF: 0.446 AC: 2293 AN: 5144

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4818

European-Finnish (FIN) AF: 0.372 AC: 3950 AN: 10610

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28649 AN: 67962

Other (OTH) AF: 0.440 AC: 931 AN: 2116

Alfa AF: 0.440 Hom.: 2872

Bravo AF: 0.507

Asia WGS AF: 0.368 AC: 1284 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.35
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2288746; hg19: chr2-241726646; COSMIC: COSV107338624; COSMIC: COSV107338624;