12-27488512-C-T

Variant summary

Our verdict is Likely benign. Variant got -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. 13/21 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

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.843
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMCO2NM_001395208.2 linkc.565C>T p.Arg189Trp missense_variant Exon 6 of 9 ENST00000535986.2 NP_001382137.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMCO2ENST00000535986.2 linkc.565C>T p.Arg189Trp missense_variant Exon 6 of 9 5 NM_001395208.2 ENSP00000441688.1 A6NFE2
SMCO2ENST00000298876.8 linkc.415C>T p.Arg139Trp missense_variant Exon 5 of 8 5 ENSP00000298876.4 J3KNC3
SMCO2ENST00000698358.1 linkc.178C>T p.Arg60Trp missense_variant Exon 3 of 6 ENSP00000513681.1 A0A8V8TM60
SMCO2ENST00000538647.1 linkn.169-7168C>T intron_variant Intron 2 of 2 5

Frequencies

GnomAD3 genomes
AF:
0.00162
AC:
246
AN:
152052
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.00132
AC:
195
AN:
147722
Hom.:
1
AF XY:
0.00125
AC XY:
98
AN XY:
78294
show subpopulations
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 SAS exome
AF:
0.0000480
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
show subpopulations
Gnomad4 AFR exome
AF:
0.000675
Gnomad4 AMR exome
AF:
0.000761
Gnomad4 ASJ exome
AF:
0.0000400
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000106
Gnomad4 FIN exome
AF:
0.000448
Gnomad4 NFE exome
AF:
0.00362
Gnomad4 OTH exome
AF:
0.00195
GnomAD4 genome
AF:
0.00162
AC:
246
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.00148
AC XY:
110
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.000602
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.00310
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.00227
Hom.:
0
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

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 20, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.565C>T (p.R189W) alteration is located in exon 6 (coding exon 5) of the SMCO2 gene. This alteration results from a C to T substitution at nucleotide position 565, causing the arginine (R) at amino acid position 189 to be replaced by a tryptophan (W). 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
0.13
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
14
DANN
Benign
0.97
DEOGEN2
Benign
0.074
T;T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.046
N
LIST_S2
Benign
0.48
T;T;.
M_CAP
Benign
0.0028
T
MetaRNN
Benign
0.0069
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
.;L;L
PrimateAI
Benign
0.28
T
PROVEAN
Uncertain
-2.4
N;D;D
REVEL
Benign
0.022
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.012
D;D;D
Polyphen
0.0
.;B;B
Vest4
0.11
MVP
0.088
ClinPred
0.044
T
GERP RS
-0.20
Varity_R
0.097
gMVP
0.031

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148846851; hg19: chr12-27641445; API