chr12-27488512-C-T

Variant names:

• chr12-27488512-C-T
• rs148846851
• NM_001395208.2:c.565C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001395208.2(SMCO2):​c.565C>T​(p.Arg189Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,538,666 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (14 hom.)
• Consequence: SMCO2 NM_001395208.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.843
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395208.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCO2	NM_001395208.2	MANE Select	c.565C>T	p.Arg189Trp	missense	Exon 6 of 9	NP_001382137.1	A6NFE2
	SMCO2	NM_001145010.3		c.565C>T	p.Arg189Trp	missense	Exon 6 of 9	NP_001138482.1	A6NFE2
	SMCO2	NM_001387218.3		c.178C>T	p.Arg60Trp	missense	Exon 3 of 6	NP_001374147.1	A0A8V8TM60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCO2	ENST00000535986.2	TSL:5 MANE Select	c.565C>T	p.Arg189Trp	missense	Exon 6 of 9	ENSP00000441688.1	A6NFE2
	SMCO2	ENST00000298876.8	TSL:5	c.415C>T	p.Arg139Trp	missense	Exon 5 of 8	ENSP00000298876.4	J3KNC3
	SMCO2	ENST00000698358.1		c.178C>T	p.Arg60Trp	missense	Exon 3 of 6	ENSP00000513681.1	A0A8V8TM60

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00132 AC: 195 AN: 147722 AF XY: 0.00125

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000858

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000312

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00294 AC: 4076 AN: 1386496 Hom.: 14 Cov.: 30 AF XY: 0.00289 AC XY: 1972 AN XY: 683116

African (AFR) AF: 0.000675 AC: 21 AN: 31134

American (AMR) AF: 0.000761 AC: 26 AN: 34174

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 25016

East Asian (EAS) AF: 0.00 AC: 0 AN: 35074

South Asian (SAS) AF: 0.000106 AC: 8 AN: 75694

European-Finnish (FIN) AF: 0.000448 AC: 22 AN: 49152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00362 AC: 3886 AN: 1073072

Other (OTH) AF: 0.00195 AC: 112 AN: 57524

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74396

African (AFR) AF: 0.000602 AC: 25 AN: 41506

American (AMR) AF: 0.000393 AC: 6 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 68014

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00223 Hom.: 3

Bravo AF: 0.00161

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00283 AC: 9

ExAC AF: 0.000774 AC: 19

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.84
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.022
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		0.0	B
Vest4		0.11
MVP		0.088
ClinPred		0.044	T
GERP RS		-0.20
Varity_R		0.097
gMVP		0.031
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148846851; hg19: chr12-27641445; COSMIC: COSV106102209;