rs531544601

Variant names:

• chr17-4999978-G-A
• rs531544601
• NM_006612.6:c.-28+8G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006612.6(KIF1C):​c.-28+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 469,290 control chromosomes in the GnomAD database, including 2 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: KIF1C NM_006612.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001321
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.709
• Publications: 0 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-4999978-G-A is Benign according to our data. Variant chr17-4999978-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 515316.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000256 (39/152368) while in subpopulation NFE AF = 0.000514 (35/68038). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.-28+8G>A		splice_region intron	N/A	NP_006603.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	ENST00000320785.10	TSL:1 MANE Select	c.-28+8G>A		splice_region intron	N/A	ENSP00000320821.5	O43896
	KIF1C	ENST00000948910.1		c.-28+8G>A		splice_region intron	N/A	ENSP00000618969.1
	KIF1C	ENST00000948913.1		c.-27-242G>A		intron	N/A	ENSP00000618972.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000514

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000278 AC: 88 AN: 316922 Hom.: 2 Cov.: 0 AF XY: 0.000264 AC XY: 44 AN XY: 166860

African (AFR) AF: 0.00 AC: 0 AN: 9568

American (AMR) AF: 0.00 AC: 0 AN: 12520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9776

East Asian (EAS) AF: 0.00 AC: 0 AN: 20394

South Asian (SAS) AF: 0.00 AC: 0 AN: 38006

European-Finnish (FIN) AF: 0.000216 AC: 4 AN: 18484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1410

European-Non Finnish (NFE) AF: 0.000424 AC: 80 AN: 188538

Other (OTH) AF: 0.000219 AC: 4 AN: 18226

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74514

African (AFR) AF: 0.0000721 AC: 3 AN: 41584

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.000514 AC: 35 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000208

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs531544601; hg19: chr17-4903273;