rs1063353

Variant names:

• chr2-240774229-A-G
• rs1063353
• NM_001244008.2:c.991T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-240774229-A-G
• chr2-240774229-A-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.991T>C​(p.Leu331Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.366 in 1,608,610 control chromosomes in the GnomAD database, including 114,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16938 hom., cov: 33)
  • Exomes 𝑓: 0.36 (97144 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.67
• Publications: 19 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.266).
• BP6: Variant 2-240774229-A-G is Benign according to our data. Variant chr2-240774229-A-G is described in ClinVar as Benign. ClinVar VariationId is 129396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.991T>C	p.Leu331Leu	synonymous_variant	Exon 12 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.991T>C	p.Leu331Leu	synonymous_variant	Exon 12 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67904 AN: 151984 Hom.: 16921 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.374 AC: 92453 AN: 247338 AF XY: 0.365

Gnomad AFR exome AF: 0.682

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.588

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.380

GnomAD4 exome AF: 0.358 AC: 520723 AN: 1456508 Hom.: 97144 Cov.: 31 AF XY: 0.355 AC XY: 257111 AN XY: 724676

African (AFR) AF: 0.693 AC: 23127 AN: 33386

American (AMR) AF: 0.313 AC: 13960 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 8089 AN: 26014

East Asian (EAS) AF: 0.604 AC: 23905 AN: 39582

South Asian (SAS) AF: 0.310 AC: 26600 AN: 85848

European-Finnish (FIN) AF: 0.322 AC: 17173 AN: 53278

Middle Eastern (MID) AF: 0.361 AC: 2075 AN: 5750

European-Non Finnish (NFE) AF: 0.346 AC: 382971 AN: 1107926

Other (OTH) AF: 0.379 AC: 22823 AN: 60158

GnomAD4 genome AF: 0.447 AC: 67953 AN: 152102 Hom.: 16938 Cov.: 33 AF XY: 0.443 AC XY: 32934 AN XY: 74358

African (AFR) AF: 0.676 AC: 28065 AN: 41488

American (AMR) AF: 0.372 AC: 5684 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1107 AN: 3470

East Asian (EAS) AF: 0.605 AC: 3129 AN: 5170

South Asian (SAS) AF: 0.327 AC: 1575 AN: 4822

European-Finnish (FIN) AF: 0.315 AC: 3336 AN: 10586

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23695 AN: 67962

Other (OTH) AF: 0.415 AC: 875 AN: 2108

Alfa AF: 0.385 Hom.: 7805

Bravo AF: 0.461

Asia WGS AF: 0.462 AC: 1610 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Sep 23, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Mar 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 30 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		6.7
Mutation Taster		=97/3	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: rs1063353; hg19: chr2-241713646; COSMIC: COSV57491042; COSMIC: COSV57491042;