rs79290524

Variant names:

• chr17-5004971-C-G
• rs79290524
• NM_006612.6:c.1136C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS1

The NM_006612.6(KIF1C):​c.1136C>G​(p.Ala379Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000499 in 1,614,240 control chromosomes in the GnomAD database, including 1 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 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.95
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 17-5004971-C-G is Benign according to our data. Variant chr17-5004971-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468849.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000322 (49/152362) while in subpopulation NFE AF = 0.000603 (41/68032). AF 95% confidence interval is 0.000457. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	NM_006612.6	MANE Select	c.1136C>G	p.Ala379Gly	missense	Exon 13 of 23	NP_006603.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	ENST00000320785.10	TSL:1 MANE Select	c.1136C>G	p.Ala379Gly	missense	Exon 13 of 23	ENSP00000320821.5

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 251392 AF XY: 0.000456

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000518 AC: 757 AN: 1461878 Hom.: 1 Cov.: 32 AF XY: 0.000534 AC XY: 388 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53410

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000621 AC: 691 AN: 1112006

Other (OTH) AF: 0.000464 AC: 28 AN: 60396

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74510

African (AFR) AF: 0.0000721 AC: 3 AN: 41588

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000626 Hom.: 1

Bravo AF: 0.000306

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.79	N
PhyloP100		4.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.18
Sift	Benign	0.16	T
Sift4G	Benign	0.19	T
Polyphen		0.58	P
Vest4		0.38
MVP		0.65
MPC		0.40
ClinPred		0.032	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.12
gMVP		0.48
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.92		Position offset: -1
DS_DL_spliceai		0.23		Position offset: 29

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

Other links and lift over

dbSNP: rs79290524; hg19: chr17-4908266;