Genetic Variant ITM2C:p.Arg188Trp (chr2-230877400-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030926.6(ITM2C):c.562A>T(p.Arg188Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ITM2C
NM_030926.6 missense, splice_region

Scores

Splicing: ADA: 0.2465

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.56

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2C	NM_030926.6 link	c.562A>T	p.Arg188Trp	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000326427.11	NP_112188.1	Q9NQX7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITM2C	ENST00000326427.11 link	c.562A>T	p.Arg188Trp	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_030926.6	ENSP00000322730.6	Q9NQX7-1
ITM2C	ENST00000326407.10 link	c.451A>T	p.Arg151Trp	missense_variant, splice_region_variant	Exon 4 of 5	1		ENSP00000322100.6	Q9NQX7-3
ITM2C	ENST00000335005.10 link	c.421A>T	p.Arg141Trp	missense_variant, splice_region_variant	Exon 4 of 5	1		ENSP00000335121.6	Q9NQX7-2
ITM2C	ENST00000409704.6 link	c.376A>T	p.Arg126Trp	missense_variant, splice_region_variant	Exon 5 of 6	5		ENSP00000387242.2	B8ZZM6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250100

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135326

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461110

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726866

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562A>T (p.R188W) alteration is located in exon 5 (coding exon 5) of the ITM2C gene. This alteration results from a A to T substitution at nucleotide position 562, causing the arginine (R) at amino acid position 188 to be replaced by a tryptophan (W). 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

Uncertain

0.41

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;.;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;D;T;D

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.4

L;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.44

MutPred

0.34

Gain of ubiquitination at K187 (P = 0.0371);.;.;.;

MVP

0.89

MPC

0.86

ClinPred

0.92

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.25

dbscSNV1_RF

Benign

0.57

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