2-240741385-G-A

Variant names:

• chr2-240741385-G-A
• rs56024577
• NM_001244008.2:c.3641-8C>T

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.3641-8C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.279 in 1,543,814 control chromosomes in the GnomAD database, including 66,318 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5486 hom., cov: 33)
  • Exomes 𝑓: 0.28 (60832 hom.)
• Consequence: KIF1A NM_001244008.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003042
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.72
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-240741385-G-A is Benign according to our data. Variant chr2-240741385-G-A is described in ClinVar as Benign. ClinVar VariationId is 129391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

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.3641-8C>T		splice_region intron	N/A	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3716-8C>T		splice_region intron	N/A	NP_001366560.1
	KIF1A	NM_001379642.1		c.3614-8C>T		splice_region intron	N/A	NP_001366571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3641-8C>T		splice_region intron	N/A	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000492812.6	TSL:1	n.803-8C>T		splice_region intron	N/A
	KIF1A	ENST00000675932.2		c.3641-8C>T		splice_region intron	N/A	ENSP00000502786.2	A0A6Q8PHQ5

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35771 AN: 152008 Hom.: 5473 Cov.: 33

Gnomad AFR AF: 0.0604

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.240

GnomAD2 exomes AF: 0.347 AC: 57808 AN: 166444 AF XY: 0.352

Gnomad AFR exome AF: 0.0590

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.453

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.284 AC: 395390 AN: 1391688 Hom.: 60832 Cov.: 30 AF XY: 0.291 AC XY: 199666 AN XY: 686874

African (AFR) AF: 0.0524 AC: 1678 AN: 32046

American (AMR) AF: 0.482 AC: 18285 AN: 37952

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6034 AN: 24750

East Asian (EAS) AF: 0.424 AC: 15654 AN: 36960

South Asian (SAS) AF: 0.478 AC: 37511 AN: 78474

European-Finnish (FIN) AF: 0.339 AC: 13089 AN: 38620

Middle Eastern (MID) AF: 0.337 AC: 1904 AN: 5648

European-Non Finnish (NFE) AF: 0.264 AC: 284955 AN: 1079250

Other (OTH) AF: 0.281 AC: 16280 AN: 57988

GnomAD4 genome AF: 0.235 AC: 35797 AN: 152126 Hom.: 5486 Cov.: 33 AF XY: 0.247 AC XY: 18348 AN XY: 74372

African (AFR) AF: 0.0603 AC: 2504 AN: 41556

American (AMR) AF: 0.347 AC: 5300 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 813 AN: 3470

East Asian (EAS) AF: 0.431 AC: 2221 AN: 5148

South Asian (SAS) AF: 0.484 AC: 2331 AN: 4818

European-Finnish (FIN) AF: 0.335 AC: 3537 AN: 10566

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18327 AN: 67966

Other (OTH) AF: 0.248 AC: 524 AN: 2110

Alfa AF: 0.227 Hom.: 1476

Bravo AF: 0.227

Asia WGS AF: 0.438 AC: 1519 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hereditary spastic paraplegia 30 (2)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Intellectual disability, autosomal dominant 9 (1)
-	-	1	Neuropathy, hereditary sensory, type 2C (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	-0.82
CADD	Benign	5.8
DANN	Benign	0.53
PhyloP100		3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.0080
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: rs56024577; hg19: chr2-241680802; COSMIC: COSV57484858; COSMIC: COSV57484858;