12-27488523-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001395208.2(SMCO2):c.576C>G(p.Asp192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCO2 NM_001395208.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.601

Genes affected

SMCO2 (HGNC:34448): (single-pass membrane protein with coiled-coil domains 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.14650634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCO2	NM_001395208.2	c.576C>G	p.Asp192Glu	missense_variant	6/9	ENST00000535986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCO2	ENST00000535986.2	c.576C>G	p.Asp192Glu	missense_variant	6/9	5	NM_001395208.2
SMCO2	ENST00000298876.8	c.426C>G	p.Asp142Glu	missense_variant	5/8	5		P1
SMCO2	ENST00000698358.1	c.189C>G	p.Asp63Glu	missense_variant	3/6
SMCO2	ENST00000538647.1	n.169-7157C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.576C>G (p.D192E) alteration is located in exon 6 (coding exon 5) of the SMCO2 gene. This alteration results from a C to G substitution at nucleotide position 576, causing the aspartic acid (D) at amino acid position 192 to be replaced by a glutamic acid (E). 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	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	11
Dann	Benign	0.74
DEOGEN2	Benign	0.092	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.41	T;T;.
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.060
Sift	Uncertain	0.015	D;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		0.97	.;D;D
Vest4		0.071
MutPred		0.36		.;Gain of catalytic residue at G196 (P = 8e-04);Gain of catalytic residue at G196 (P = 8e-04);
MVP		0.030
ClinPred		0.43	T
GERP RS		2.4
Varity_R		0.065
gMVP		0.011

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs890995265; hg19: chr12-27641456;