rs142056835

Variant names:

• chr17-5004946-G-A
• rs142056835
• NM_006612.6:c.1111G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-5004946-G-A
• chr17-5004946-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006612.6(KIF1C):​c.1111G>A​(p.Ala371Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,614,248 control chromosomes in the GnomAD database, including 20 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (19 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.13
• Publications: 10 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 Gene-Disease associations (from GenCC):

• spastic ataxia 2

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01151219).
• BP6: Variant 17-5004946-G-A is Benign according to our data. Variant chr17-5004946-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 424675.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00355 (541/152368) while in subpopulation NFE AF = 0.00525 (357/68040). AF 95% confidence interval is 0.0048. There are 1 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 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.1111G>A	p.Ala371Thr	missense	Exon 13 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.1111G>A	p.Ala371Thr	missense	Exon 13 of 23	ENSP00000320821.5	O43896
	KIF1C	ENST00000948910.1		c.1141G>A	p.Ala381Thr	missense	Exon 13 of 23	ENSP00000618969.1
	KIF1C	ENST00000948913.1		c.1141G>A	p.Ala381Thr	missense	Exon 12 of 22	ENSP00000618972.1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 541 AN: 152250 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00337 AC: 847 AN: 251406 AF XY: 0.00327

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00434 AC: 6342 AN: 1461880 Hom.: 19 Cov.: 32 AF XY: 0.00428 AC XY: 3109 AN XY: 727238

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.00253 AC: 113 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.00687 AC: 367 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00497 AC: 5528 AN: 1112008

Other (OTH) AF: 0.00323 AC: 195 AN: 60396

GnomAD4 genome AF: 0.00355 AC: 541 AN: 152368 Hom.: 1 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74516

African (AFR) AF: 0.000505 AC: 21 AN: 41590

American (AMR) AF: 0.00431 AC: 66 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00593 AC: 63 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00525 AC: 357 AN: 68040

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00415 Hom.: 5

Bravo AF: 0.00308

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00351 AC: 426

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00344

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary spastic paraplegia (2)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic ataxia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.70	N
REVEL	Benign	0.15
Sift	Benign	0.81	T
Sift4G	Benign	0.65	T
Polyphen		0.92	P
Vest4		0.17
MVP		0.73
MPC		0.44
ClinPred		0.030	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.10
gMVP		0.46
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs142056835; hg19: chr17-4908241; COSMIC: COSV99077308; COSMIC: COSV99077308;