2-240741216-G-T

Variant names:

• chr2-240741216-G-T
• rs4414678
• NM_001244008.2:c.3749+53C>A

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.3749+53C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,269,880 control chromosomes in the GnomAD database, including 99,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13833 hom., cov: 32)
  • Exomes 𝑓: 0.38 (85459 hom.)
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.77
• Publications: 4 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=-0.97).
• BP6: Variant 2-240741216-G-T is Benign according to our data. Variant chr2-240741216-G-T is described in ClinVar as Benign. ClinVar VariationId is 670535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3749+53C>A		intron	N/A	NP_001230937.1
	KIF1A	NM_001379631.1		c.3824+53C>A		intron	N/A	NP_001366560.1
	KIF1A	NM_001379642.1		c.3722+53C>A		intron	N/A	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3749+53C>A		intron	N/A	ENSP00000438388.1
	KIF1A	ENST00000492812.6	TSL:1	n.911+53C>A		intron	N/A
	KIF1A	ENST00000675932.2		c.3749+53C>A		intron	N/A	ENSP00000502786.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63342 AN: 151818 Hom.: 13805 Cov.: 32

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.406

GnomAD4 exome AF: 0.382 AC: 426997 AN: 1117944 Hom.: 85459 AF XY: 0.388 AC XY: 217913 AN XY: 561482

African (AFR) AF: 0.493 AC: 12960 AN: 26268

American (AMR) AF: 0.562 AC: 19340 AN: 34428

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 8552 AN: 22968

East Asian (EAS) AF: 0.542 AC: 18681 AN: 34444

South Asian (SAS) AF: 0.563 AC: 40864 AN: 72582

European-Finnish (FIN) AF: 0.433 AC: 15576 AN: 35992

Middle Eastern (MID) AF: 0.466 AC: 1961 AN: 4204

European-Non Finnish (NFE) AF: 0.345 AC: 289345 AN: 838118

Other (OTH) AF: 0.403 AC: 19718 AN: 48940

GnomAD4 genome AF: 0.417 AC: 63417 AN: 151936 Hom.: 13833 Cov.: 32 AF XY: 0.426 AC XY: 31635 AN XY: 74238

African (AFR) AF: 0.481 AC: 19961 AN: 41460

American (AMR) AF: 0.450 AC: 6866 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1240 AN: 3470

East Asian (EAS) AF: 0.568 AC: 2914 AN: 5134

South Asian (SAS) AF: 0.574 AC: 2756 AN: 4804

European-Finnish (FIN) AF: 0.435 AC: 4589 AN: 10554

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23850 AN: 67944

Other (OTH) AF: 0.413 AC: 867 AN: 2098

Alfa AF: 0.372 Hom.: 27725

Bravo AF: 0.421

Asia WGS AF: 0.571 AC: 1982 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.59
DANN	Benign	0.69
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4414678; hg19: chr2-241680633; COSMIC: COSV57486496; COSMIC: COSV57486496;