Genetic Variant ITM2C:p.Ala25Thr (chr2-230865098-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030926.6(ITM2C):c.73G>A(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,367,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ITM2C
NM_030926.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08969283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2C	NM_030926.6 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 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.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 6	1	NM_030926.6	ENSP00000322730.6		Q9NQX7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.31e-7

AC:

AN:

1367692

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

674176

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:

9.42e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73G>A (p.A25T) alteration is located in exon 1 (coding exon 1) of the ITM2C gene. This alteration results from a G to A substitution at nucleotide position 73, causing the alanine (A) at amino acid position 25 to be replaced by a threonine (T). 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

0.074

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.0057

T;T;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.090

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;L;L;L

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.040

N;N;N;N

REVEL

Benign

0.024

Sift

Benign

0.60

T;T;T;T

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.011, 0.048, 0.066

.;B;B;B

Vest4

0.11, 0.33, 0.20

MutPred

0.16

Gain of glycosylation at A25 (P = 0.0027);Gain of glycosylation at A25 (P = 0.0027);Gain of glycosylation at A25 (P = 0.0027);Gain of glycosylation at A25 (P = 0.0027);

MVP

0.42

MPC

0.23

ClinPred

0.082

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.057

gMVP

0.28

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over