chr2-240766810-C-T

Variant names:

• chr2-240766810-C-T
• rs11681427
• NM_001244008.2:c.1684+105G>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.1684+105G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 674,322 control chromosomes in the GnomAD database, including 12,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2207 hom., cov: 31)
  • Exomes 𝑓: 0.19 (9937 hom.)
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.739
• Publications: 3 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 2-240766810-C-T is Benign according to our data. Variant chr2-240766810-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.1684+105G>A		intron_variant	Intron 19 of 48	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.1684+105G>A		intron_variant	Intron 19 of 48	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23228 AN: 149312 Hom.: 2203 Cov.: 31

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.0831

Gnomad SAS AF: 0.0884

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.186 AC: 97668 AN: 524894 Hom.: 9937 AF XY: 0.183 AC XY: 50343 AN XY: 275420

African (AFR) AF: 0.0540 AC: 808 AN: 14968

American (AMR) AF: 0.113 AC: 3269 AN: 29018

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 4532 AN: 15654

East Asian (EAS) AF: 0.0773 AC: 2089 AN: 27022

South Asian (SAS) AF: 0.0942 AC: 4844 AN: 51420

European-Finnish (FIN) AF: 0.205 AC: 7451 AN: 36410

Middle Eastern (MID) AF: 0.196 AC: 734 AN: 3754

European-Non Finnish (NFE) AF: 0.215 AC: 68513 AN: 318204

Other (OTH) AF: 0.191 AC: 5428 AN: 28444

GnomAD4 genome AF: 0.156 AC: 23238 AN: 149428 Hom.: 2207 Cov.: 31 AF XY: 0.153 AC XY: 11155 AN XY: 72746

African (AFR) AF: 0.0516 AC: 2091 AN: 40562

American (AMR) AF: 0.153 AC: 2278 AN: 14926

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 985 AN: 3458

East Asian (EAS) AF: 0.0833 AC: 400 AN: 4800

South Asian (SAS) AF: 0.0899 AC: 423 AN: 4704

European-Finnish (FIN) AF: 0.191 AC: 1939 AN: 10134

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.213 AC: 14418 AN: 67568

Other (OTH) AF: 0.179 AC: 373 AN: 2078

Alfa AF: 0.105 Hom.: 199

Bravo AF: 0.148

Asia WGS AF: 0.0810 AC: 282 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.3
DANN	Benign	0.47
PhyloP100		-0.74
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: rs11681427; hg19: chr2-241706227; COSMIC: COSV57489047; COSMIC: COSV57489047;