rs1063353

Positions:

• chr2-240774229-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.991T>C​(p.Leu331=) variant causes a synonymous change. The variant allele was found at a frequency of 0.366 in 1,608,610 control chromosomes in the GnomAD database, including 114,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16938 hom., cov: 33)
  • Exomes 𝑓: 0.36 (97144 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-240774229-A-G is Benign according to our data. Variant chr2-240774229-A-G is described in ClinVar as [Benign]. Clinvar id is 129396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240774229-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.991T>C	p.Leu331=	synonymous_variant	12/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.991T>C	p.Leu331=	synonymous_variant	12/49	5	NM_001244008.2	ENSP00000438388

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67904 AN: 151984 Hom.: 16921 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.374 AC: 92453 AN: 247338 Hom.: 18794 AF XY: 0.365 AC XY: 48975 AN XY: 134304

Gnomad AFR exome AF: 0.682

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.588

Gnomad SAS exome AF: 0.316

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.380

GnomAD4 exome AF: 0.358 AC: 520723 AN: 1456508 Hom.: 97144 Cov.: 31 AF XY: 0.355 AC XY: 257111 AN XY: 724676

Gnomad4 AFR exome AF: 0.693

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.311

Gnomad4 EAS exome AF: 0.604

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.346

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.447 AC: 67953 AN: 152102 Hom.: 16938 Cov.: 33 AF XY: 0.443 AC XY: 32934 AN XY: 74358

Gnomad4 AFR AF: 0.676

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.605

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.415

Alfa AF: 0.383 Hom.: 6093

Bravo AF: 0.461

Asia WGS AF: 0.462 AC: 1610 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 23, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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 12, 2016

- -

Hereditary spastic paraplegia 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.57
CADD	Benign	10
DANN	Benign	0.71

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: rs1063353; hg19: chr2-241713646; COSMIC: COSV57491042; COSMIC: COSV57491042;