chr17-5020056-C-T

Variant names:

• chr17-5020056-C-T
• rs370888080
• NM_006612.6:c.1727C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_006612.6(KIF1C):​c.1727C>T​(p.Thr576Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,599,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.601
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09794405).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000105 (16/152138) while in subpopulation AMR AF = 0.000917 (14/15268). AF 95% confidence interval is 0.000554. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1727C>T	p.Thr576Met	missense	Exon 19 of 23	NP_006603.2
	KIF1C-AS1	NR_120665.2		n.38G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	ENST00000320785.10	TSL:1 MANE Select	c.1727C>T	p.Thr576Met	missense	Exon 19 of 23	ENSP00000320821.5	O43896
	KIF1C	ENST00000948910.1		c.1757C>T	p.Thr586Met	missense	Exon 19 of 23	ENSP00000618969.1
	KIF1C	ENST00000948913.1		c.1757C>T	p.Thr586Met	missense	Exon 18 of 22	ENSP00000618972.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000357 AC: 8 AN: 224386 AF XY: 0.0000249

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000297 AC: 43 AN: 1446878 Hom.: 0 Cov.: 30 AF XY: 0.0000237 AC XY: 17 AN XY: 718222

African (AFR) AF: 0.00 AC: 0 AN: 33210

American (AMR) AF: 0.000188 AC: 8 AN: 42454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39126

South Asian (SAS) AF: 0.0000479 AC: 4 AN: 83524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000253 AC: 28 AN: 1104626

Other (OTH) AF: 0.0000501 AC: 3 AN: 59832

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.000917 AC: 14 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spastic ataxia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-0.60
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.24
Sift	Uncertain	0.025	D
Sift4G	Benign	0.061	T
Polyphen		0.018	B
Vest4		0.091
MVP		0.63
MPC		0.38
ClinPred		0.15	T
GERP RS		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.083
gMVP		0.67
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs370888080; hg19: chr17-4923351; COSMIC: COSV100297202;