rs199996308

Positions:

• chr2-240758467-G-A

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.2475C>T​(p.Tyr825Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000895 in 1,604,988 control chromosomes in the GnomAD database, including 19 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 0.00073 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (18 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -1.85

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-240758467-G-A is Benign according to our data. Variant chr2-240758467-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=6}. Variant chr2-240758467-G-A is described in Lovd as [Likely_benign]. Variant chr2-240758467-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000729 (111/152288) while in subpopulation SAS AF= 0.0162 (78/4824). AF 95% confidence interval is 0.0133. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2475C>T	p.Tyr825Tyr	synonymous_variant	26/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2475C>T	p.Tyr825Tyr	synonymous_variant	26/49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00180 AC: 423 AN: 235624 Hom.: 4 AF XY: 0.00236 AC XY: 302 AN XY: 128094

Gnomad AFR exome AF: 0.0000688

Gnomad AMR exome AF: 0.000153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.000912 AC: 1325 AN: 1452700 Hom.: 18 Cov.: 31 AF XY: 0.00126 AC XY: 910 AN XY: 722014

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000252

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000917

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74456

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000230

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 25, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2017	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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

KIF1A: BP4, BP7, BS1, BS2 -

Hereditary spastic paraplegia 30 Benign:1

Likely 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 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

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.1
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: rs199996308; hg19: chr2-241697884; COSMIC: COSV57485354;