rs35945835

Positions:

• chr2-240761259-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.2235C>T​(p.Ala745=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 129385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240761259-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2235C>T	p.Ala745=	synonymous_variant	24/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2235C>T	p.Ala745=	synonymous_variant	24/49	5	NM_001244008.2	ENSP00000438388

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

GnomAD3 exomes AF: 0.0372 AC: 9269 AN: 248974 Hom.: 254 AF XY: 0.0376 AC XY: 5079 AN XY: 135048

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 SAS exome AF: 0.0162

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

Gnomad4 AFR exome AF: 0.00846

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.0912

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0491

Gnomad4 OTH exome AF: 0.0427

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

Gnomad4 AFR AF: 0.00880

Gnomad4 AMR AF: 0.0397

Gnomad4 ASJ AF: 0.0962

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.0499

Gnomad4 OTH AF: 0.0421

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2016

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 18, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary spastic paraplegia 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs35945835; hg19: chr2-241700676;