dbSNP rs202233918: ITM2C:p.Val186Met (chr2-230876962-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_030926.6(ITM2C):c.556G>A(p.Val186Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ITM2C
NM_030926.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.82

Variant links:

Genes affected

ITM2C (HGNC:6175): (integral membrane protein 2C) Enables amyloid-beta binding activity. Involved in negative regulation of neuron projection development and neuron differentiation. Located in several cellular components, including Golgi apparatus; lysosome; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ITM2C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32849008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2C	NM_030926.6 link	c.556G>A	p.Val186Met	missense_variant	Exon 4 of 6	ENST00000326427.11	NP_112188.1	Q9NQX7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITM2C	ENST00000326427.11 link	c.556G>A	p.Val186Met	missense_variant	Exon 4 of 6	1	NM_030926.6	ENSP00000322730.6		Q9NQX7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251232

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1454262

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724078

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000200

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556G>A (p.V186M) alteration is located in exon 4 (coding exon 4) of the ITM2C gene. This alteration results from a G to A substitution at nucleotide position 556, causing the valine (V) at amino acid position 186 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

.;T;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.81

.;T;T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.65

.;N;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.6

N;N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.093

T;D;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

1.0, 0.95

.;D;P;.;.

Vest4

0.37, 0.38, 0.34

MVP

0.74

MPC

0.39

ClinPred

0.53

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over