rs2241683

Variant names:

• chr2-240725384-C-T
• rs2241683
• NM_001244008.2:c.4143G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001244008.2(KIF1A):​c.4143G>A​(p.Pro1381Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,612,268 control chromosomes in the GnomAD database, including 3,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (376 hom., cov: 32)
  • Exomes 𝑓: 0.015 (2717 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.14
• Publications: 8 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.053).
• BP6: Variant 2-240725384-C-T is Benign according to our data. Variant chr2-240725384-C-T is described in ClinVar as Benign. ClinVar VariationId is 129393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.4143G>A	p.Pro1381Pro	synonymous_variant	Exon 40 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.4143G>A	p.Pro1381Pro	synonymous_variant	Exon 40 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3808 AN: 152168 Hom.: 374 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0929

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0392 AC: 9686 AN: 246782 AF XY: 0.0339

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.00429

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0148 AC: 21641 AN: 1459982 Hom.: 2717 Cov.: 31 AF XY: 0.0141 AC XY: 10234 AN XY: 726232

African (AFR) AF: 0.0130 AC: 435 AN: 33474

American (AMR) AF: 0.105 AC: 4663 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26106

East Asian (EAS) AF: 0.337 AC: 13364 AN: 39672

South Asian (SAS) AF: 0.00732 AC: 631 AN: 86188

European-Finnish (FIN) AF: 0.00378 AC: 197 AN: 52134

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5766

European-Non Finnish (NFE) AF: 0.000718 AC: 798 AN: 1111700

Other (OTH) AF: 0.0243 AC: 1464 AN: 60348

GnomAD4 genome AF: 0.0251 AC: 3823 AN: 152286 Hom.: 376 Cov.: 32 AF XY: 0.0281 AC XY: 2096 AN XY: 74460

African (AFR) AF: 0.0138 AC: 574 AN: 41576

American (AMR) AF: 0.0934 AC: 1430 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.305 AC: 1573 AN: 5150

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4826

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68018

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.00904 Hom.: 120

Bravo AF: 0.0303

Asia WGS AF: 0.123 AC: 425 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 28, 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. -

-

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. -

Dec 13, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.68
CADD	Benign	0.91
DANN	Benign	0.56
PhyloP100		-5.1
Mutation Taster		=98/2	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: rs2241683; hg19: chr2-241664801; COSMIC: COSV57484145; COSMIC: COSV57484145;