2-240713870-A-G

Variant names:

• chr2-240713870-A-G
• rs4613
• ENST00000460788.5:n.5427T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.*3494T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,820 control chromosomes in the GnomAD database, including 18,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18291 hom., cov: 34)
  • Exomes 𝑓: 0.35 (36 hom.)
• Consequence: KIF1A NM_001244008.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.159
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-240713870-A-G is Benign according to our data. Variant chr2-240713870-A-G is described in ClinVar as [Benign]. Clinvar id is 335210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.*3494T>C		3_prime_UTR_variant	Exon 49 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.*3494T>C		3_prime_UTR_variant	Exon 49 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70787 AN: 152056 Hom.: 18248 Cov.: 34

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.466

GnomAD4 exome AF: 0.348 AC: 225 AN: 646 Hom.: 36 Cov.: 0 AF XY: 0.364 AC XY: 139 AN XY: 382

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.341 AC: 47 AN: 138

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.337 AC: 128 AN: 380

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.365 AC: 38 AN: 104

Other (OTH) AF: 0.444 AC: 8 AN: 18

GnomAD4 genome AF: 0.466 AC: 70886 AN: 152174 Hom.: 18291 Cov.: 34 AF XY: 0.464 AC XY: 34545 AN XY: 74406

African (AFR) AF: 0.691 AC: 28660 AN: 41502

American (AMR) AF: 0.519 AC: 7935 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1810 AN: 3472

East Asian (EAS) AF: 0.267 AC: 1383 AN: 5184

South Asian (SAS) AF: 0.224 AC: 1079 AN: 4826

European-Finnish (FIN) AF: 0.399 AC: 4224 AN: 10588

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24295 AN: 67986

Other (OTH) AF: 0.465 AC: 983 AN: 2114

Alfa AF: 0.405 Hom.: 16148

Bravo AF: 0.490

Asia WGS AF: 0.290 AC: 1014 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 30 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.41
DANN	Benign	0.35
PhyloP100		-0.16
Mutation Taster		=100/0	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: rs4613; hg19: chr2-241653287; COSMIC: COSV57494241; COSMIC: COSV57494241;