rs35663732

Positions:

• chr2-240767340-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.1503A>G​(p.Pro501=) 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

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 -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 [Likely_benign]. Clinvar id is 129384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240767340-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.1503A>G	p.Pro501=	synonymous_variant	18/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.1503A>G	p.Pro501=	synonymous_variant	18/49	5	NM_001244008.2	ENSP00000438388

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

GnomAD3 exomes AF: 0.0195 AC: 4854 AN: 248720 Hom.: 49 AF XY: 0.0207 AC XY: 2795 AN XY: 135070

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 SAS exome AF: 0.0317

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

Gnomad4 AFR exome AF: 0.00810

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.00423

Gnomad4 SAS exome AF: 0.0303

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0205

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

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.00464

Gnomad4 SAS AF: 0.0314

Gnomad4 FIN AF: 0.0286

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0191 Hom.: 19

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 15, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 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

Nov 29, 2021

- -

Hereditary spastic paraplegia 30 Benign:1

Likely 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 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

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	-0.90
CADD	Benign	0.085
DANN	Benign	0.55

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: rs35663732; hg19: chr2-241706757; COSMIC: COSV57485119; COSMIC: COSV57485119;