rs771217469

Positions:

• chr2-240722483-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001244008.2(KIF1A):​c.4638C>T​(p.Asn1546=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,547,304 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.959

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-240722483-G-A is Benign according to our data. Variant chr2-240722483-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211289.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr2-240722483-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.959 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000105 (147/1395060) while in subpopulation SAS AF= 0.000607 (48/79138). AF 95% confidence interval is 0.000469. There are 0 homozygotes in gnomad4_exome. There are 84 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.4638C>T	p.Asn1546=	synonymous_variant	43/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.4638C>T	p.Asn1546=	synonymous_variant	43/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000871 AC: 13 AN: 149308 Hom.: 0 AF XY: 0.0000999 AC XY: 8 AN XY: 80050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000528

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 147 AN: 1395060 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 84 AN XY: 688084

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000607

Gnomad4 FIN exome AF: 0.0000214

Gnomad4 NFE exome AF: 0.0000834

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74416

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000496 Hom.: 0

Bravo AF: 0.0000604

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 19, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 02, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.69

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: rs771217469; hg19: chr2-241661900;