2-240788210-C-A

Variant names:

• chr2-240788210-C-A
• rs141052770
• NM_001244008.2:c.204G>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.204G>T​(p.Ala68Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,613,776 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (24 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.696

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-240788210-C-A is Benign according to our data. Variant chr2-240788210-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 335282.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=1}. Variant chr2-240788210-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.696 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00321 (489/152308) while in subpopulation NFE AF= 0.00557 (379/68024). AF 95% confidence interval is 0.00511. There are 1 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.204G>T	p.Ala68Ala	synonymous_variant	Exon 4 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.204G>T	p.Ala68Ala	synonymous_variant	Exon 4 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00288 AC: 716 AN: 248494 Hom.: 3 AF XY: 0.00293 AC XY: 396 AN XY: 135042

Gnomad AFR exome AF: 0.000773

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000720

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.00504

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00454 AC: 6639 AN: 1461468 Hom.: 24 Cov.: 35 AF XY: 0.00444 AC XY: 3227 AN XY: 727018

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.000526

Gnomad4 NFE exome AF: 0.00553

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.00321 AC: 489 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74480

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00557

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00338

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00628

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF1A: BP4, BP7, BS2 -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Oct 14, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 30 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Jun 24, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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 08, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 02, 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	-0.62
CADD	Benign	7.7
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs141052770; hg19: chr2-241727627; COSMIC: COSV57487097; COSMIC: COSV57487097;