Variant 9-104100147-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006444.3(SMC2):c.535A>G(p.Ile179Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,579,640 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 0 hom. )

Consequence

SMC2
NM_006444.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

Variant links:

Genes affected

SMC2 (HGNC:14011): (structural maintenance of chromosomes 2) Predicted to enable ATP binding activity; chromatin binding activity; and single-stranded DNA binding activity. Involved in mitotic chromosome condensation. Located in condensed chromosome; cytoplasm; and nuclear lumen. Part of condensin complex. [provided by Alliance of Genome Resources, Apr 2022]

SMC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036794126).

BS2

High AC in GnomAd at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC2	NM_006444.3 linkuse as main transcript	c.535A>G	p.Ile179Val	missense_variant	6/25	ENST00000374793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC2	ENST00000374793.8 linkuse as main transcript	c.535A>G	p.Ile179Val	missense_variant	6/25	1	NM_006444.3	P1	O95347-1
SMC2	ENST00000286398.11 linkuse as main transcript	c.535A>G	p.Ile179Val	missense_variant	6/25	1		P1	O95347-1
SMC2	ENST00000374787.7 linkuse as main transcript	c.535A>G	p.Ile179Val	missense_variant	6/25	2		P1	O95347-1
SMC2	ENST00000440179.5 linkuse as main transcript	c.100A>G	p.Ile34Val	missense_variant	4/6	3

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000563

AC:

123

AN:

218524

Hom.:

AF XY:

0.000587

AC XY:

AN XY:

119316

show subpopulations

Gnomad AFR exome

AF:

0.0000666

Gnomad AMR exome

AF:

0.000214

Gnomad ASJ exome

AF:

0.000704

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000381

Gnomad NFE exome

AF:

0.000949

Gnomad OTH exome

AF:

0.000573

GnomAD4 exome

AF:

0.000729

AC:

1040

AN:

1427434

Hom.:

Cov.:

AF XY:

0.000709

AC XY:

503

AN XY:

709938

show subpopulations

Gnomad4 AFR exome

AF:

0.000129

Gnomad4 AMR exome

AF:

0.000308

Gnomad4 ASJ exome

AF:

0.000364

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000507

Gnomad4 NFE exome

AF:

0.000863

Gnomad4 OTH exome

AF:

0.000645

GnomAD4 genome

AF:

0.000493

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000798

Hom.:

Bravo

AF:

0.000419

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000561

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.535A>G (p.I179V) alteration is located in exon 6 (coding exon 5) of the SMC2 gene. This alteration results from a A to G substitution at nucleotide position 535, causing the isoleucine (I) at amino acid position 179 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

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.12

T;T;T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

T;T;.;.

M_CAP

Benign

0.0059

MetaRNN

Benign

0.037

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;L;L

MutationTaster

Benign

0.60

D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.22

N;N;N;N

REVEL

Benign

0.047

Sift

Benign

0.055

T;T;T;T

Sift4G

Benign

0.30

T;T;T;T

Polyphen

0.0080

B;.;B;B

Vest4

0.33

MVP

0.17

MPC

0.098

ClinPred

0.019

GERP RS

2.0

Varity_R

0.047

gMVP

0.39

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

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