rs7576602

Variant names:

• chr2-240745275-C-T
• rs7576602
• NM_001244008.2:c.3465+152G>A

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.3465+152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,144 control chromosomes in the GnomAD database, including 2,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.16 (2245 hom., cov: 33)
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.244
• Publications: 2 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=-0.88).
• BP6: Variant 2-240745275-C-T is Benign according to our data. Variant chr2-240745275-C-T is described in ClinVar as Benign. ClinVar VariationId is 1281671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.3465+152G>A		intron_variant	Intron 32 of 48	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.3465+152G>A		intron_variant	Intron 32 of 48	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24187 AN: 152028 Hom.: 2244 Cov.: 33

Gnomad AFR AF: 0.0714

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.0897

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.186

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

GnomAD4 genome AF: 0.159 AC: 24194 AN: 152144 Hom.: 2245 Cov.: 33 AF XY: 0.157 AC XY: 11642 AN XY: 74372

African (AFR) AF: 0.0713 AC: 2959 AN: 41520

American (AMR) AF: 0.153 AC: 2333 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 988 AN: 3470

East Asian (EAS) AF: 0.0787 AC: 405 AN: 5148

South Asian (SAS) AF: 0.0912 AC: 440 AN: 4824

European-Finnish (FIN) AF: 0.189 AC: 2008 AN: 10602

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14373 AN: 67984

Other (OTH) AF: 0.186 AC: 392 AN: 2108

Alfa AF: 0.176 Hom.: 400

Bravo AF: 0.154

Asia WGS AF: 0.0800 AC: 278 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.37
PhyloP100		-0.24
PromoterAI		-0.0026	Neutral
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: rs7576602; hg19: chr2-241684692; COSMIC: COSV107338342; COSMIC: COSV107338342;