rs370913170

Variant names:

• chr2-240741337-C-T
• rs370913170
• NM_001244008.2:c.3681G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-240741337-C-T
• chr2-240741337-C-G

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.3681G>A​(p.Pro1227Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,593,740 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (4 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -9.19
• Publications: 1 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, G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

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

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

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 (REVEL=0.058).
• BP6: Variant 2-240741337-C-T is Benign according to our data. Variant chr2-240741337-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 391226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000328 (50/152328) while in subpopulation SAS AF = 0.00414 (20/4826). AF 95% confidence interval is 0.00275. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3681G>A	p.Pro1227Pro	synonymous	Exon 35 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3756G>A	p.Pro1252Pro	synonymous	Exon 35 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3654G>A	p.Pro1218Pro	synonymous	Exon 34 of 49	NP_001366571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3681G>A	p.Pro1227Pro	synonymous	Exon 35 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000492812.6	TSL:1	n.843G>A		non_coding_transcript_exon	Exon 3 of 16
	KIF1A	ENST00000675932.2		c.3681G>A	p.Pro1227Pro	synonymous	Exon 35 of 49	ENSP00000502786.2	A0A6Q8PHQ5

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000586 AC: 128 AN: 218388 AF XY: 0.000689

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000560

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000604

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.000909

GnomAD4 exome AF: 0.000612 AC: 882 AN: 1441412 Hom.: 4 Cov.: 31 AF XY: 0.000679 AC XY: 486 AN XY: 715854

African (AFR) AF: 0.0000903 AC: 3 AN: 33234

American (AMR) AF: 0.000466 AC: 20 AN: 42944

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25890

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39020

South Asian (SAS) AF: 0.00308 AC: 258 AN: 83684

European-Finnish (FIN) AF: 0.0000221 AC: 1 AN: 45322

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5748

European-Non Finnish (NFE) AF: 0.000506 AC: 560 AN: 1105766

Other (OTH) AF: 0.000485 AC: 29 AN: 59804

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74486

African (AFR) AF: 0.0000722 AC: 3 AN: 41572

American (AMR) AF: 0.000458 AC: 7 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000298

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (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	-0.75
CADD	Benign	0.017
DANN	Benign	0.70
PhyloP100		-9.2
Mutation Taster		=97/3	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: rs370913170; hg19: chr2-241680754; COSMIC: COSV57491078; COSMIC: COSV57491078;