rs35945835

Variant names:

• chr2-240761259-G-A
• rs35945835
• NM_001244008.2:c.2235C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.2235C>T​(p.Ala745Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.0431 in 1,613,412 control chromosomes in the GnomAD database, including 1,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (132 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1634 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.35
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-240761259-G-A is Benign according to our data. Variant chr2-240761259-G-A is described in ClinVar as Benign. ClinVar VariationId is 129385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2235C>T	p.Ala745Ala	synonymous_variant	Exon 24 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2235C>T	p.Ala745Ala	synonymous_variant	Exon 24 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5126 AN: 152270 Hom.: 134 Cov.: 33

Gnomad AFR AF: 0.00885

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0398

Gnomad ASJ AF: 0.0962

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0372 AC: 9269 AN: 248974 AF XY: 0.0376

Gnomad AFR exome AF: 0.00768

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0887

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0516

Gnomad OTH exome AF: 0.0621

GnomAD4 exome AF: 0.0441 AC: 64456 AN: 1461024 Hom.: 1634 Cov.: 31 AF XY: 0.0435 AC XY: 31644 AN XY: 726726

African (AFR) AF: 0.00846 AC: 283 AN: 33466

American (AMR) AF: 0.0362 AC: 1619 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0912 AC: 2381 AN: 26120

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.0164 AC: 1415 AN: 86230

European-Finnish (FIN) AF: 0.0200 AC: 1065 AN: 53348

Middle Eastern (MID) AF: 0.101 AC: 571 AN: 5650

European-Non Finnish (NFE) AF: 0.0491 AC: 54540 AN: 1111476

Other (OTH) AF: 0.0427 AC: 2576 AN: 60338

GnomAD4 genome AF: 0.0336 AC: 5116 AN: 152388 Hom.: 132 Cov.: 33 AF XY: 0.0313 AC XY: 2336 AN XY: 74524

African (AFR) AF: 0.00880 AC: 366 AN: 41594

American (AMR) AF: 0.0397 AC: 608 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0962 AC: 334 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4832

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10632

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0499 AC: 3398 AN: 68038

Other (OTH) AF: 0.0421 AC: 89 AN: 2114

Alfa AF: 0.0456 Hom.: 95

Bravo AF: 0.0356

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.0576

EpiControl AF: 0.0597

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

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. -

Apr 17, 2014

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. -

Inborn genetic diseases Benign:1

Mar 16, 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 18, 2021

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 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.44
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		4.3
Mutation Taster		=58/42	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: rs35945835; hg19: chr2-241700676; COSMIC: COSV107338424;