rs62637652

Variant names:

• chr2-240760724-G-A
• rs62637652
• NM_001244008.2:c.2385C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240760724-G-A
• chr2-240760724-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.2385C>T​(p.Ala795Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,588,182 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 33)
  • Exomes 𝑓: 0.014 (177 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.99
• Publications: 3 publications found

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-240760724-G-A is Benign according to our data. Variant chr2-240760724-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00968 (1475/152310) while in subpopulation NFE AF = 0.014 (953/68034). AF 95% confidence interval is 0.0133. There are 12 homozygotes in GnomAd4. There are 759 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244008.2. 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
	KIF1A	NM_001244008.2	MANE Select	c.2385C>T	p.Ala795Ala	synonymous	Exon 25 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.2460C>T	p.Ala820Ala	synonymous	Exon 25 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2358C>T	p.Ala786Ala	synonymous	Exon 24 of 49	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.2385C>T	p.Ala795Ala	synonymous	Exon 25 of 49	ENSP00000438388.1
	KIF1A	ENST00000675932.2		c.2385C>T	p.Ala795Ala	synonymous	Exon 25 of 49	ENSP00000502786.2
	KIF1A	ENST00000675314.2		c.2514C>T	p.Ala838Ala	synonymous	Exon 26 of 50	ENSP00000502584.2

Frequencies

GnomAD3 genomes AF: 0.00969 AC: 1475 AN: 152192 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0118 AC: 2624 AN: 223078 AF XY: 0.0121

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00459

Gnomad EAS exome AF: 0.000128

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0143 AC: 20590 AN: 1435872 Hom.: 177 Cov.: 31 AF XY: 0.0142 AC XY: 10138 AN XY: 711736

African (AFR) AF: 0.00213 AC: 69 AN: 32324

American (AMR) AF: 0.00309 AC: 128 AN: 41458

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 111 AN: 25434

East Asian (EAS) AF: 0.0000789 AC: 3 AN: 38010

South Asian (SAS) AF: 0.0110 AC: 909 AN: 82534

European-Finnish (FIN) AF: 0.0295 AC: 1552 AN: 52692

Middle Eastern (MID) AF: 0.00478 AC: 27 AN: 5646

European-Non Finnish (NFE) AF: 0.0155 AC: 17001 AN: 1098602

Other (OTH) AF: 0.0134 AC: 790 AN: 59172

GnomAD4 genome AF: 0.00968 AC: 1475 AN: 152310 Hom.: 12 Cov.: 33 AF XY: 0.0102 AC XY: 759 AN XY: 74478

African (AFR) AF: 0.00260 AC: 108 AN: 41576

American (AMR) AF: 0.00327 AC: 50 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

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

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4824

European-Finnish (FIN) AF: 0.0284 AC: 301 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0140 AC: 953 AN: 68034

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00966 Hom.: 10

Bravo AF: 0.00760

Asia WGS AF: 0.00433 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.8
DANN	Benign	0.91
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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: rs62637652; hg19: chr2-241700141;