12-27501945-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001395208.2(SMCO2):c.856A>G(p.Ile286Val) 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. 14/19 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMCO2 NM_001395208.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.434

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045910418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCO2	NM_001395208.2	c.856A>G	p.Ile286Val	missense_variant	9/9	ENST00000535986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCO2	ENST00000535986.2	c.856A>G	p.Ile286Val	missense_variant	9/9	5	NM_001395208.2
SMCO2	ENST00000298876.8	c.706A>G	p.Ile236Val	missense_variant	8/8	5		P1
SMCO2	ENST00000698358.1	c.469A>G	p.Ile157Val	missense_variant	6/6
SMCO2	ENST00000541168.1	n.720A>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1389990 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 685336

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 18, 2023

The c.856A>G (p.I286V) alteration is located in exon 9 (coding exon 8) of the SMCO2 gene. This alteration results from a A to G substitution at nucleotide position 856, causing the isoleucine (I) at amino acid position 286 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	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.44
Dann	Uncertain	0.98
DEOGEN2	Benign	0.023	T;T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.55	T;T;.
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.35	.;B;B
Vest4		0.14
MutPred		0.27		.;Gain of catalytic residue at D289 (P = 0.0309);Gain of catalytic residue at D289 (P = 0.0309);
MVP		0.014
ClinPred		0.13	T
GERP RS		-0.73
Varity_R		0.022
gMVP		0.075

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: chr12-27654878;