2-240760762-C-G

Position:

• chr2-240760762-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001244008.2(KIF1A):​c.2347G>C​(p.Asp783His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30346638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2347G>C	p.Asp783His	missense_variant	25/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2347G>C	p.Asp783His	missense_variant	25/49	5	NM_001244008.2	ENSP00000438388

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Nov 02, 2023

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF1A protein function. ClinVar contains an entry for this variant (Variation ID: 1482329). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 774 of the KIF1A protein (p.Asp774His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Benign	0.072
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	.;D;D;.;.;.;.;.;.;.;.;.;D
REVEL	Benign	0.15
Sift	Benign	0.14	.;T;T;.;.;.;.;.;.;.;.;.;T
Sift4G	Uncertain	0.059	.;T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.20	B;.;.;.;.;.;.;B;.;.;.;.;P
Vest4		0.37, 0.37
MutPred		0.25		Gain of glycosylation at P769 (P = 0.173);.;Gain of glycosylation at P769 (P = 0.173);.;.;Gain of glycosylation at P769 (P = 0.173);Gain of glycosylation at P769 (P = 0.173);Gain of glycosylation at P769 (P = 0.173);Gain of glycosylation at P769 (P = 0.173);.;Gain of glycosylation at P769 (P = 0.173);.;.;
MVP		0.59
MPC		0.53
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.20
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs1441080561; hg19: chr2-241700179;