2-240742347-G-A

Variant names:

• chr2-240742347-G-A
• rs3755534
• NM_001244008.2:c.3640+582C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001244008.2(KIF1A):​c.3640+582C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 151,994 control chromosomes in the GnomAD database, including 3,915 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3915 hom., cov: 32)
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.676
• 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, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.3640+582C>T		intron_variant	Intron 34 of 48	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.3640+582C>T		intron_variant	Intron 34 of 48	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30539 AN: 151876 Hom.: 3903 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.188

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.201 AC: 30581 AN: 151994 Hom.: 3915 Cov.: 32 AF XY: 0.198 AC XY: 14684 AN XY: 74298

African (AFR) AF: 0.366 AC: 15154 AN: 41426

American (AMR) AF: 0.132 AC: 2012 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 602 AN: 3472

East Asian (EAS) AF: 0.117 AC: 605 AN: 5160

South Asian (SAS) AF: 0.104 AC: 499 AN: 4804

European-Finnish (FIN) AF: 0.132 AC: 1393 AN: 10584

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9752 AN: 67964

Other (OTH) AF: 0.186 AC: 392 AN: 2104

Alfa AF: 0.148 Hom.: 3687

Bravo AF: 0.211

Asia WGS AF: 0.139 AC: 482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.33
PhyloP100		-0.68
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: rs3755534; hg19: chr2-241681764;