2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCC

Variant names:

• chr2-240757423-ATCCTCCTCC-A
• rs10594016
• NM_001244008.2:c.2745_2753delGGAGGAGGA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_001244008.2(KIF1A):​c.2745_2753delGGAGGAGGA​(p.Glu915_Glu917del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000107 in 1,482,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: KIF1A NM_001244008.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.36

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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001244008.2
• BP6: Variant 2-240757423-ATCCTCCTCC-A is Benign according to our data. Variant chr2-240757423-ATCCTCCTCC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1341632.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000349 (48/137634) while in subpopulation AFR AF= 0.000994 (38/38246). AF 95% confidence interval is 0.000744. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2745_2753delGGAGGAGGA	p.Glu915_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2745_2753delGGAGGAGGA	p.Glu915_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 48 AN: 137554 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000215

Gnomad SAS AF: 0.000244

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000967

Gnomad OTH AF: 0.00106

GnomAD3 exomes AF: 0.000182 AC: 20 AN: 110140 Hom.: 0 AF XY: 0.000100 AC XY: 6 AN XY: 59702

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.000279

Gnomad ASJ exome AF: 0.000159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000316

GnomAD4 exome AF: 0.0000818 AC: 110 AN: 1344924 Hom.: 0 AF XY: 0.0000890 AC XY: 59 AN XY: 663212

Gnomad4 AFR exome AF: 0.000851

Gnomad4 AMR exome AF: 0.000177

Gnomad4 ASJ exome AF: 0.0000418

Gnomad4 EAS exome AF: 0.0000585

Gnomad4 SAS exome AF: 0.0000799

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.000143

GnomAD4 genome AF: 0.000349 AC: 48 AN: 137634 Hom.: 0 Cov.: 0 AF XY: 0.000300 AC XY: 20 AN XY: 66660

Gnomad4 AFR AF: 0.000994

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000215

Gnomad4 SAS AF: 0.000245

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000967

Gnomad4 OTH AF: 0.00105

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jun 07, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 3 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge; Located in an alternate transcript of the gene -

KIF1A-related disorder Uncertain:1

Dec 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KIF1A c.2745_2753del9 variant is predicted to result in an in-frame deletion (p.Glu915_Glu917del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Benign:1

Aug 26, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10594016; hg19: chr2-241696840;