12-27470725-T-G

Variant names:

• chr12-27470725-T-G
• rs73086401
• NM_001395208.2:c.94T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001395208.2(SMCO2):​c.94T>G​(p.Phe32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,398,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SMCO2 NM_001395208.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.642

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34404752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCO2	NM_001395208.2	c.94T>G	p.Phe32Val	missense_variant	Exon 2 of 9	ENST00000535986.2	NP_001382137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCO2	ENST00000535986.2	c.94T>G	p.Phe32Val	missense_variant	Exon 2 of 9	5	NM_001395208.2	ENSP00000441688.1
SMCO2	ENST00000298876.8	c.94T>G	p.Phe32Val	missense_variant	Exon 2 of 8	5		ENSP00000298876.4
SMCO2	ENST00000698358.1	c.-3-4061T>G		intron_variant	Intron 1 of 5			ENSP00000513681.1
SMCO2	ENST00000543991.1	n.104T>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000122 AC: 17 AN: 1398844 Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5 AN XY: 689938

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: 0.0000158

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.94T>G (p.F32V) alteration is located in exon 2 (coding exon 1) of the SMCO2 gene. This alteration results from a T to G substitution at nucleotide position 94, causing the phenylalanine (F) at amino acid position 32 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.74
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.47	T;T;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.87	.;P;P
Vest4		0.55
MutPred		0.30		Gain of catalytic residue at N37 (P = 0.0266);Gain of catalytic residue at N37 (P = 0.0266);Gain of catalytic residue at N37 (P = 0.0266);
MVP		0.014
ClinPred		0.43	T
GERP RS		0.82
Varity_R		0.17
gMVP		0.037

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs73086401; hg19: chr12-27623658;