rs141052770

Variant names:

• chr2-240788210-C-A
• rs141052770
• NM_001244008.2:c.204G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240788210-C-A
• chr2-240788210-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.204G>T​(p.Ala68Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,613,776 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A68A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (24 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.696
• 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, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-240788210-C-A is Benign according to our data. Variant chr2-240788210-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 335282.
• BP7: Synonymous conserved (PhyloP=-0.696 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00321 (489/152308) while in subpopulation NFE AF = 0.00557 (379/68024). AF 95% confidence interval is 0.00511. There are 1 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 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.204G>T	p.Ala68Ala	synonymous	Exon 4 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.204G>T	p.Ala68Ala	synonymous	Exon 4 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.204G>T	p.Ala68Ala	synonymous	Exon 4 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.204G>T	p.Ala68Ala	synonymous	Exon 4 of 49	ENSP00000438388.1
	KIF1A	ENST00000675932.2		c.204G>T	p.Ala68Ala	synonymous	Exon 4 of 49	ENSP00000502786.2
	KIF1A	ENST00000675314.2		c.333G>T	p.Ala111Ala	synonymous	Exon 5 of 50	ENSP00000502584.2

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00288 AC: 716 AN: 248494 AF XY: 0.00293

Gnomad AFR exome AF: 0.000773

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.00504

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00454 AC: 6639 AN: 1461468 Hom.: 24 Cov.: 35 AF XY: 0.00444 AC XY: 3227 AN XY: 727018

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86226

European-Finnish (FIN) AF: 0.000526 AC: 28 AN: 53280

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00553 AC: 6148 AN: 1111814

Other (OTH) AF: 0.00338 AC: 204 AN: 60368

GnomAD4 genome AF: 0.00321 AC: 489 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74480

African (AFR) AF: 0.000818 AC: 34 AN: 41572

American (AMR) AF: 0.00111 AC: 17 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00557 AC: 379 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00338

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00628

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (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	-0.62
CADD	Benign	7.7
DANN	Benign	0.59
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs141052770; hg19: chr2-241727627; COSMIC: COSV57487097; COSMIC: COSV57487097;