rs148404628

Positions:

• chr17-5020485-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006612.6(KIF1C):​c.1751-7T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,604,314 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (73 hom.)
• Consequence: KIF1C NM_006612.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002009
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.408

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-5020485-T-A is Benign according to our data. Variant chr17-5020485-T-A is described in ClinVar as [Benign]. Clinvar id is 385057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-5020485-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00705 (1073/152274) while in subpopulation NFE AF= 0.0111 (757/68006). AF 95% confidence interval is 0.0105. There are 9 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1C	NM_006612.6	c.1751-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320785.10	NP_006603.2
KIF1C	XM_005256424.3	c.1751-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_005256481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1C	ENST00000320785.10	c.1751-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006612.6	ENSP00000320821	P1
KIF1C	ENST00000573815.1	n.293-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1073 AN: 152156 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00699 AC: 1713 AN: 245130 Hom.: 13 AF XY: 0.00739 AC XY: 982 AN XY: 132922

Gnomad AFR exome AF: 0.000809

Gnomad AMR exome AF: 0.00689

Gnomad ASJ exome AF: 0.00746

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00342

Gnomad FIN exome AF: 0.00318

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00898 AC: 13038 AN: 1452040 Hom.: 73 Cov.: 33 AF XY: 0.00903 AC XY: 6511 AN XY: 721122

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.00693

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00412

Gnomad4 FIN exome AF: 0.00265

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00864

GnomAD4 genome AF: 0.00705 AC: 1073 AN: 152274 Hom.: 9 Cov.: 32 AF XY: 0.00670 AC XY: 499 AN XY: 74456

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00810

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0101 Hom.: 2

Bravo AF: 0.00736

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KIF1C: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2016

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. -

Spastic ataxia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.8
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
dbscSNV1_RF	Benign	0.10
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: rs148404628; hg19: chr17-4923780;