chr2-240788042-G-C

Variant names:

• chr2-240788042-G-C
• rs368803931
• NM_001244008.2:c.363+9C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001244008.2(KIF1A):​c.363+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.16 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.03
• Publications: 0 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=-0.89).
• BP6: Variant 2-240788042-G-C is Benign according to our data. Variant chr2-240788042-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 701810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.363+9C>G		intron	N/A	NP_001230937.1
	KIF1A	NM_001379631.1		c.363+9C>G		intron	N/A	NP_001366560.1
	KIF1A	NM_001379642.1		c.363+9C>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.363+9C>G		intron	N/A	ENSP00000438388.1
	KIF1A	ENST00000675932.2		c.363+9C>G		intron	N/A	ENSP00000502786.2
	KIF1A	ENST00000675314.2		c.492+9C>G		intron	N/A	ENSP00000502584.2

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 135 AN: 107706 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000345

Gnomad EAS AF: 0.00220

Gnomad SAS AF: 0.00231

Gnomad FIN AF: 0.00343

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000895

Gnomad OTH AF: 0.000684

GnomAD2 exomes AF: 0.0565 AC: 5851 AN: 103482 AF XY: 0.0509

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.0787

Gnomad EAS exome AF: 0.0743

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0989

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.155 AC: 60139 AN: 387228 Hom.: 4 Cov.: 18 AF XY: 0.152 AC XY: 29710 AN XY: 195854

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.163 AC: 1516 AN: 9280

American (AMR) AF: 0.256 AC: 3903 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 1284 AN: 9364

East Asian (EAS) AF: 0.0908 AC: 887 AN: 9768

South Asian (SAS) AF: 0.171 AC: 5476 AN: 32102

European-Finnish (FIN) AF: 0.0670 AC: 1674 AN: 24998

Middle Eastern (MID) AF: 0.0715 AC: 195 AN: 2726

European-Non Finnish (NFE) AF: 0.159 AC: 42673 AN: 267966

Other (OTH) AF: 0.160 AC: 2531 AN: 15800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00126 AC: 136 AN: 107786 Hom.: 0 Cov.: 30 AF XY: 0.00165 AC XY: 84 AN XY: 50772

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00139 AC: 39 AN: 28022

American (AMR) AF: 0.00157 AC: 14 AN: 8910

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 1 AN: 2902

East Asian (EAS) AF: 0.00220 AC: 8 AN: 3634

South Asian (SAS) AF: 0.00231 AC: 7 AN: 3032

European-Finnish (FIN) AF: 0.00343 AC: 18 AN: 5250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.000895 AC: 48 AN: 53652

Other (OTH) AF: 0.000678 AC: 1 AN: 1474

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0116 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.57
DANN	Benign	0.35
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs368803931; hg19: chr2-241727459;