Variant chr2-17718217-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001142286.2(SMC6):c.952C>G(p.Leu318Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,430,144 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: not found (cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

SMC6
NM_001142286.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Variant links:

Genes affected

SMC6 (HGNC:20466): (structural maintenance of chromosomes 6) Enables ubiquitin protein ligase binding activity. Involved in several processes, including cellular senescence; positive regulation of chromosome segregation; and telomere maintenance via recombination. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

SMC6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032300472).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC6	NM_001142286.2 linkuse as main transcript	c.952C>G	p.Leu318Val	missense_variant	12/28	ENST00000448223.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC6	ENST00000448223.7 linkuse as main transcript	c.952C>G	p.Leu318Val	missense_variant	12/28	1	NM_001142286.2	P1	Q96SB8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000259

AC:

AN:

231248

Hom.:

AF XY:

0.0000241

AC XY:

AN XY:

124728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000235

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000559

AC:

AN:

1430144

Hom.:

Cov.:

AF XY:

0.00000422

AC XY:

AN XY:

710162

show subpopulations

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:

0.000103

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

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

Oct 25, 2023

The c.952C>G (p.L318V) alteration is located in exon 12 (coding exon 10) of the SMC6 gene. This alteration results from a C to G substitution at nucleotide position 952, causing the leucine (L) at amino acid position 318 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

0.078

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.34

DEOGEN2

Benign

0.039

T;T;T;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.78

.;.;T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.032

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.9

N;N;N;.;.

MutationTaster

Benign

0.97

N;N;N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.37

N;N;N;N;.

REVEL

Benign

0.084

Sift

Benign

1.0

T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.0030

B;B;B;B;.

Vest4

0.22

MutPred

0.50

Gain of MoRF binding (P = 0.0963);Gain of MoRF binding (P = 0.0963);Gain of MoRF binding (P = 0.0963);.;Gain of MoRF binding (P = 0.0963);

MVP

0.22

MPC

0.30

ClinPred

0.069

GERP RS

3.3

Varity_R

0.035

gMVP

0.54

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