NM_001244008.2:c.1503A>G

Variant names:

• chr2-240767340-T-C
• rs35663732
• NM_001244008.2:c.1503A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.1503A>G​(p.Pro501Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,612,896 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (31 hom., cov: 33)
  • Exomes 𝑓: 0.019 (316 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.10
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-240767340-T-C is Benign according to our data. Variant chr2-240767340-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2741/152190) while in subpopulation SAS AF = 0.0314 (151/4814). AF 95% confidence interval is 0.0273. There are 31 homozygotes in GnomAd4. There are 1425 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 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.1503A>G	p.Pro501Pro	synonymous	Exon 18 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.1578A>G	p.Pro526Pro	synonymous	Exon 18 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.1476A>G	p.Pro492Pro	synonymous	Exon 17 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.1503A>G	p.Pro501Pro	synonymous	Exon 18 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.1503A>G	p.Pro501Pro	synonymous	Exon 18 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.1632A>G	p.Pro544Pro	synonymous	Exon 19 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2742 AN: 152072 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0195 AC: 4854 AN: 248720 AF XY: 0.0207

Gnomad AFR exome AF: 0.00933

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00486

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0188 AC: 27462 AN: 1460706 Hom.: 316 Cov.: 31 AF XY: 0.0195 AC XY: 14137 AN XY: 726682

African (AFR) AF: 0.00810 AC: 271 AN: 33466

American (AMR) AF: 0.0127 AC: 567 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 562 AN: 26120

East Asian (EAS) AF: 0.00423 AC: 168 AN: 39698

South Asian (SAS) AF: 0.0303 AC: 2613 AN: 86164

European-Finnish (FIN) AF: 0.0249 AC: 1324 AN: 53210

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5766

European-Non Finnish (NFE) AF: 0.0186 AC: 20638 AN: 1111240

Other (OTH) AF: 0.0205 AC: 1237 AN: 60346

GnomAD4 genome AF: 0.0180 AC: 2741 AN: 152190 Hom.: 31 Cov.: 33 AF XY: 0.0192 AC XY: 1425 AN XY: 74398

African (AFR) AF: 0.0105 AC: 434 AN: 41528

American (AMR) AF: 0.0141 AC: 215 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.00464 AC: 24 AN: 5170

South Asian (SAS) AF: 0.0314 AC: 151 AN: 4814

European-Finnish (FIN) AF: 0.0286 AC: 304 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1476 AN: 67974

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0182 Hom.: 26

Bravo AF: 0.0164

Asia WGS AF: 0.0240 AC: 86 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0206

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	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	-0.90
CADD	Benign	0.085
DANN	Benign	0.55
PhyloP100		-1.1
Mutation Taster		=97/3	polymorphism (auto)

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: rs35663732; hg19: chr2-241706757; COSMIC: COSV57485119; COSMIC: COSV57485119;