2-17716229-T-C

Variant names:

• chr2-17716229-T-C
• rs1303046068
• NM_001142286.2:c.1382A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142286.2(SMC6):​c.1382A>G​(p.Tyr461Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 6.9e-7 (0 hom.)
• Consequence: SMC6 NM_001142286.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82

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]

ACMG classification

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=0.12846074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC6	NM_001142286.2	c.1382A>G	p.Tyr461Cys	missense_variant	Exon 15 of 28	ENST00000448223.7	NP_001135758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC6	ENST00000448223.7	c.1382A>G	p.Tyr461Cys	missense_variant	Exon 15 of 28	1	NM_001142286.2	ENSP00000404092.2
SMC6	ENST00000351948.8	c.1382A>G	p.Tyr461Cys	missense_variant	Exon 14 of 27	1		ENSP00000323439.4
SMC6	ENST00000446852.5	c.1460A>G	p.Tyr487Cys	missense_variant	Exon 16 of 20	1		ENSP00000408644.1
SMC6	ENST00000402989.5	c.1382A>G	p.Tyr461Cys	missense_variant	Exon 17 of 30	2		ENSP00000384539.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248890 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134552

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459836 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726228

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.048	T;T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.83	.;.;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.083
Sift	Benign	0.12	T;T;T;T
Sift4G	Uncertain	0.052	T;T;T;T
Polyphen		0.52	P;P;P;P
Vest4		0.42
MutPred		0.36		Loss of catalytic residue at Y461 (P = 0.0542);Loss of catalytic residue at Y461 (P = 0.0542);Loss of catalytic residue at Y461 (P = 0.0542);.;
MVP		0.34
MPC		0.42
ClinPred		0.083	T
GERP RS		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.44

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

Other links and lift over

dbSNP: rs1303046068; hg19: chr2-17897496;