2-240719886-C-G

Variant names:

• chr2-240719886-C-G
• rs377032453
• NM_001244008.2:c.4909G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001244008.2(KIF1A):​c.4909G>C​(p.Glu1637Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1637K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.26
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28778717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.4909G>C	p.Glu1637Gln	missense_variant	Exon 46 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.4909G>C	p.Glu1637Gln	missense_variant	Exon 46 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459374 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725954

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000224 AC: 1 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111460

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.016
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	.;T;T;T;T;T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.;M;.;.;.;.;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	.;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.072	.;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.46	.;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.62	P;.;.;.;.;.;.;P;.;.;.;.;.;.
Vest4		0.41
MutPred		0.20		Loss of solvent accessibility (P = 0.0172);.;.;.;.;.;.;Loss of solvent accessibility (P = 0.0172);.;.;.;.;.;.;
MVP		0.55
MPC		1.1
ClinPred		0.84	D
GERP RS		4.2
Varity_R		0.085
gMVP		0.42
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377032453; hg19: chr2-241659303;