rs375972461

Variant names:

• chr2-240766936-C-G
• rs375972461
• NM_001244008.2:c.1663G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-240766936-C-G
• chr2-240766936-C-T

Variant summary

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

The NM_001244008.2(KIF1A):​c.1663G>C​(p.Asp555His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,824 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. D555N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.822
• 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=0.39121413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.1663G>C	p.Asp555His	missense_variant	Exon 19 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.1663G>C	p.Asp555His	missense_variant	Exon 19 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458824 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725484

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110960

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	0.0029	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	.;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;L;.;.;.;.;.
PhyloP100		0.82
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	.;N;N;.;.;.;.;.;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.027	.;D;D;.;.;.;.;.;.;.;.;.;D
Sift4G	Benign	0.12	.;T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.81	P;.;.;.;.;.;.;P;.;.;.;.;D
Vest4		0.21, 0.23
MutPred		0.52		Loss of phosphorylation at S545 (P = 0.1665);.;Loss of phosphorylation at S545 (P = 0.1665);.;.;Loss of phosphorylation at S545 (P = 0.1665);Loss of phosphorylation at S545 (P = 0.1665);Loss of phosphorylation at S545 (P = 0.1665);Loss of phosphorylation at S545 (P = 0.1665);.;Loss of phosphorylation at S545 (P = 0.1665);.;.;
MVP		0.66
MPC		1.4
ClinPred		0.55	D
GERP RS		3.8
Varity_R		0.36
gMVP		0.86
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs375972461; hg19: chr2-241706353;