2-230875725-G-T

Variant names:

• chr2-230875725-G-T
• NM_030926.6:c.367G>T

Variant summary

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

The NM_030926.6(ITM2C):​c.367G>T​(p.Asp123Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ITM2C NM_030926.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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]

ACMG classification

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	c.367G>T	p.Asp123Tyr	missense_variant	Exon 3 of 6	ENST00000326427.11	NP_112188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITM2C	ENST00000326427.11	c.367G>T	p.Asp123Tyr	missense_variant	Exon 3 of 6	1	NM_030926.6	ENSP00000322730.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.367G>T (p.D123Y) alteration is located in exon 3 (coding exon 3) of the ITM2C gene. This alteration results from a G to T substitution at nucleotide position 367, causing the aspartic acid (D) at amino acid position 123 to be replaced by a tyrosine (Y). 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	0.33
BayesDel_addAF	Benign	0.0038	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;T;.;.;T;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.4	.;.;L;.;L;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D
Polyphen		0.81, 0.99, 0.88	.;.;P;D;P;.;.;.
Vest4		0.30, 0.36, 0.33, 0.34
MutPred		0.46		Gain of methylation at K119 (P = 0.0367);.;Gain of methylation at K119 (P = 0.0367);.;Gain of methylation at K119 (P = 0.0367);.;.;.;
MVP		0.76
MPC		0.49
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.71

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.

Other links and lift over

hg19: chr2-231740440;