chr2-240767340-T-C

Variant names:

• chr2-240767340-T-C
• rs35663732
• NM_001244008.2:c.1503A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.1503A>G​(p.Pro501Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,612,896 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (31 hom., cov: 33)
  • Exomes 𝑓: 0.019 (316 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.10
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-240767340-T-C is Benign according to our data. Variant chr2-240767340-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2741/152190) while in subpopulation SAS AF = 0.0314 (151/4814). AF 95% confidence interval is 0.0273. There are 31 homozygotes in GnomAd4. There are 1425 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.1503A>G	p.Pro501Pro	synonymous_variant	Exon 18 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.1503A>G	p.Pro501Pro	synonymous_variant	Exon 18 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2742 AN: 152072 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0195 AC: 4854 AN: 248720 AF XY: 0.0207

Gnomad AFR exome AF: 0.00933

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00486

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0188 AC: 27462 AN: 1460706 Hom.: 316 Cov.: 31 AF XY: 0.0195 AC XY: 14137 AN XY: 726682

African (AFR) AF: 0.00810 AC: 271 AN: 33466

American (AMR) AF: 0.0127 AC: 567 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 562 AN: 26120

East Asian (EAS) AF: 0.00423 AC: 168 AN: 39698

South Asian (SAS) AF: 0.0303 AC: 2613 AN: 86164

European-Finnish (FIN) AF: 0.0249 AC: 1324 AN: 53210

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5766

European-Non Finnish (NFE) AF: 0.0186 AC: 20638 AN: 1111240

Other (OTH) AF: 0.0205 AC: 1237 AN: 60346

GnomAD4 genome AF: 0.0180 AC: 2741 AN: 152190 Hom.: 31 Cov.: 33 AF XY: 0.0192 AC XY: 1425 AN XY: 74398

African (AFR) AF: 0.0105 AC: 434 AN: 41528

American (AMR) AF: 0.0141 AC: 215 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.00464 AC: 24 AN: 5170

South Asian (SAS) AF: 0.0314 AC: 151 AN: 4814

European-Finnish (FIN) AF: 0.0286 AC: 304 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1476 AN: 67974

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0182 Hom.: 26

Bravo AF: 0.0164

Asia WGS AF: 0.0240 AC: 86 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0206

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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. -

Feb 20, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 09, 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

Nov 29, 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: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Feb 03, 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	-0.90
CADD	Benign	0.085
DANN	Benign	0.55
PhyloP100		-1.1
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: rs35663732; hg19: chr2-241706757; COSMIC: COSV57485119; COSMIC: COSV57485119;