Genetic Variant SMC6:p.Val664Met (chr2-17707235-C-T) – 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_001142286.2(SMC6):c.1990G>A(p.Val664Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SMC6
NM_001142286.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.913

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 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=0.15724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC6	NM_001142286.2 link	c.1990G>A	p.Val664Met	missense_variant	Exon 18 of 28	ENST00000448223.7	NP_001135758.1	Q96SB8-1A0A2S1ZR87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC6	ENST00000448223.7 link	c.1990G>A	p.Val664Met	missense_variant	Exon 18 of 28	1	NM_001142286.2	ENSP00000404092.2		Q96SB8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438086

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000246

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1990G>A (p.V664M) alteration is located in exon 18 (coding exon 16) of the SMC6 gene. This alteration results from a G to A substitution at nucleotide position 1990, causing the valine (V) at amino acid position 664 to be replaced by a methionine (M). 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

0.24

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.081

T;T;T;.

Eigen

Benign

0.039

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

.;.;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.086

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.80

P;P;P;B

Vest4

0.33

MutPred

0.44

Gain of disorder (P = 0.1081);Gain of disorder (P = 0.1081);Gain of disorder (P = 0.1081);.;

MVP

0.30

MPC

0.68

ClinPred

0.85

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.69

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over