chr17-5005004-G-A

Position:

• chr17-5005004-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_006612.6(KIF1C):​c.1165+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,614,186 control chromosomes in the GnomAD database, including 29 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 0.0043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (27 hom.)
• Consequence: KIF1C NM_006612.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001659
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.226

Genes affected

KIF1C (HGNC:6317): (kinesin family member 1C) The protein encoded by this gene is a member of the kinesin-like protein family. The family members are microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. Mutations in this gene are a cause of spastic ataxia 2, autosomal recessive. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 17-5005004-G-A is Benign according to our data. Variant chr17-5005004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445377.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00432 (658/152350) while in subpopulation NFE AF= 0.00679 (462/68026). AF 95% confidence interval is 0.00628. There are 2 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1C	NM_006612.6	c.1165+4G>A		splice_region_variant, intron_variant		ENST00000320785.10	NP_006603.2
KIF1C	XM_005256424.3	c.1165+4G>A		splice_region_variant, intron_variant			XP_005256481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1C	ENST00000320785.10	c.1165+4G>A		splice_region_variant, intron_variant		1	NM_006612.6	ENSP00000320821.5

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 659 AN: 152232 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00743

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00681

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00467 AC: 1172 AN: 251166 Hom.: 2 AF XY: 0.00470 AC XY: 638 AN XY: 135776

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00758

Gnomad NFE exome AF: 0.00711

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00556 AC: 8134 AN: 1461836 Hom.: 27 Cov.: 32 AF XY: 0.00547 AC XY: 3976 AN XY: 727218

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00972

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00822

Gnomad4 NFE exome AF: 0.00629

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152350 Hom.: 2 Cov.: 32 AF XY: 0.00427 AC XY: 318 AN XY: 74494

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00743

Gnomad4 NFE AF: 0.00679

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00597 Hom.: 2

Bravo AF: 0.00357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KIF1C: BS2 -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 04, 2020

- -

Spastic ataxia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	20
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs192489748; hg19: chr17-4908299;