rs115332491

Variant names:

• chr17-5023826-G-A
• rs115332491
• NM_006612.6:c.2987G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006612.6(KIF1C):​c.2987G>A​(p.Ser996Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,518,520 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S996S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (73 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.833
• Publications: 6 publications found

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]

KIF1C-AS1 (HGNC:40324): (KIF1C antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017690659).
• BP6: Variant 17-5023826-G-A is Benign according to our data. Variant chr17-5023826-G-A is described in ClinVar as Benign. ClinVar VariationId is 468856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0144 (2196/152220) while in subpopulation EAS AF = 0.0522 (269/5158). AF 95% confidence interval is 0.047. There are 43 homozygotes in GnomAd4. There are 1041 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006612.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	NM_006612.6	MANE Select	c.2987G>A	p.Ser996Asn	missense	Exon 23 of 23	NP_006603.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	ENST00000320785.10	TSL:1 MANE Select	c.2987G>A	p.Ser996Asn	missense	Exon 23 of 23	ENSP00000320821.5	O43896
	KIF1C	ENST00000948910.1		c.3017G>A	p.Ser1006Asn	missense	Exon 23 of 23	ENSP00000618969.1
	KIF1C	ENST00000948913.1		c.3017G>A	p.Ser1006Asn	missense	Exon 22 of 22	ENSP00000618972.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 152102 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00915 AC: 1565 AN: 171012 AF XY: 0.00745

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00619

Gnomad EAS exome AF: 0.0533

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00268 AC: 3657 AN: 1366300 Hom.: 73 Cov.: 35 AF XY: 0.00247 AC XY: 1651 AN XY: 669546

African (AFR) AF: 0.0440 AC: 1327 AN: 30168

American (AMR) AF: 0.00213 AC: 62 AN: 29156

Ashkenazi Jewish (ASJ) AF: 0.00352 AC: 70 AN: 19914

East Asian (EAS) AF: 0.0443 AC: 1714 AN: 38718

South Asian (SAS) AF: 0.000920 AC: 65 AN: 70674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49610

Middle Eastern (MID) AF: 0.00265 AC: 14 AN: 5280

European-Non Finnish (NFE) AF: 0.0000628 AC: 67 AN: 1066646

Other (OTH) AF: 0.00602 AC: 338 AN: 56134

GnomAD4 genome AF: 0.0144 AC: 2196 AN: 152220 Hom.: 43 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74408

African (AFR) AF: 0.0425 AC: 1767 AN: 41542

American (AMR) AF: 0.00588 AC: 90 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.0522 AC: 269 AN: 5158

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67972

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0101 Hom.: 10

Bravo AF: 0.0167

ESP6500AA AF: 0.0434 AC: 189

ESP6500EA AF: 0.000352 AC: 3

ExAC AF: 0.00787 AC: 933

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	KIF1C-related disorder (1)
-	-	1	Spastic ataxia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.83
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.11
Sift	Benign	0.40	T
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.044
MVP		0.42
MPC		0.31
ClinPred		0.00080	T
GERP RS		0.20
Varity_R		0.022
gMVP		0.090
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs115332491; hg19: chr17-4927121; COSMIC: COSV107347224; COSMIC: COSV107347224;