NM_001244008.2:c.3749+42C>G

Variant names:

• chr2-240741227-G-C
• rs1013225
• NM_001244008.2:c.3749+42C>G

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.3749+42C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,377,184 control chromosomes in the GnomAD database, including 50,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6151 hom., cov: 33)
  • Exomes 𝑓: 0.26 (43875 hom.)
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.290
• Publications: 5 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=-0.92).
• BP6: Variant 2-240741227-G-C is Benign according to our data. Variant chr2-240741227-G-C is described in ClinVar as Benign. ClinVar VariationId is 674046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3749+42C>G		intron	N/A	NP_001230937.1
	KIF1A	NM_001379631.1		c.3824+42C>G		intron	N/A	NP_001366560.1
	KIF1A	NM_001379642.1		c.3722+42C>G		intron	N/A	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3749+42C>G		intron	N/A	ENSP00000438388.1
	KIF1A	ENST00000492812.6	TSL:1	n.911+42C>G		intron	N/A
	KIF1A	ENST00000675932.2		c.3749+42C>G		intron	N/A	ENSP00000502786.2

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41991 AN: 151888 Hom.: 6136 Cov.: 33

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.228 AC: 34202 AN: 149950 AF XY: 0.229

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.0664

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.262 AC: 320434 AN: 1225178 Hom.: 43875 Cov.: 17 AF XY: 0.259 AC XY: 158719 AN XY: 612574

African (AFR) AF: 0.341 AC: 9670 AN: 28360

American (AMR) AF: 0.150 AC: 5369 AN: 35900

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 8313 AN: 24074

East Asian (EAS) AF: 0.0535 AC: 1890 AN: 35350

South Asian (SAS) AF: 0.183 AC: 13864 AN: 75718

European-Finnish (FIN) AF: 0.272 AC: 10317 AN: 37964

Middle Eastern (MID) AF: 0.250 AC: 1190 AN: 4764

European-Non Finnish (NFE) AF: 0.276 AC: 256436 AN: 930440

Other (OTH) AF: 0.254 AC: 13385 AN: 52608

GnomAD4 genome AF: 0.277 AC: 42039 AN: 152006 Hom.: 6151 Cov.: 33 AF XY: 0.272 AC XY: 20216 AN XY: 74270

African (AFR) AF: 0.338 AC: 14033 AN: 41458

American (AMR) AF: 0.214 AC: 3268 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1215 AN: 3468

East Asian (EAS) AF: 0.0634 AC: 327 AN: 5154

South Asian (SAS) AF: 0.172 AC: 829 AN: 4816

European-Finnish (FIN) AF: 0.261 AC: 2761 AN: 10572

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18675 AN: 67946

Other (OTH) AF: 0.285 AC: 602 AN: 2110

Alfa AF: 0.205 Hom.: 676

Bravo AF: 0.276

Asia WGS AF: 0.122 AC: 429 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.28
DANN	Benign	0.34
PhyloP100		-0.29
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: rs1013225; hg19: chr2-241680644; COSMIC: COSV57505748; COSMIC: COSV57505748;