Genetic Variant SMCO2:p.Leu172Ile (chr12-27488461-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001395208.2(SMCO2):c.514T>A(p.Leu172Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000654 in 1,529,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SMCO2
NM_001395208.2 missense, splice_region

Scores

Splicing: ADA: 0.01339

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

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]

SMCO2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.21273875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCO2	NM_001395208.2 link	c.514T>A	p.Leu172Ile	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000535986.2	NP_001382137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMCO2	ENST00000535986.2 link	c.514T>A	p.Leu172Ile	missense_variant, splice_region_variant	Exon 6 of 9	5	NM_001395208.2	ENSP00000441688.1	A6NFE2
SMCO2	ENST00000298876.8 link	c.364T>A	p.Leu122Ile	missense_variant, splice_region_variant	Exon 5 of 8	5		ENSP00000298876.4	J3KNC3
SMCO2	ENST00000698358.1 link	c.127T>A	p.Leu43Ile	missense_variant, splice_region_variant	Exon 3 of 6			ENSP00000513681.1	A0A8V8TM60
SMCO2	ENST00000538647.1 link	n.169-7219T>A		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000291

AC:

AN:

1376870

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

678038

show subpopulations

Gnomad4 AFR exome

AF:

0.0000325

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:

0.0000525

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514T>A (p.L172I) alteration is located in exon 6 (coding exon 5) of the SMCO2 gene. This alteration results from a T to A substitution at nucleotide position 514, causing the leucine (L) at amino acid position 172 to be replaced by an isoleucine (I). 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

0.15

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.058

T;T;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.35

T;T;.

M_CAP

Benign

0.0075

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.4

.;M;M

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.076

Sift

Uncertain

0.021

D;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.41

MVP

0.048

ClinPred

0.84

GERP RS

2.8

Varity_R

0.39

gMVP

0.030

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.013

dbscSNV1_RF

Benign

0.080

SpliceAI score (max)

0.12

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over