chr2-17716229-T-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142286.2(SMC6):​c.1382A>C​(p.Tyr461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SMC6 NM_001142286.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03912896).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC6	NM_001142286.2	c.1382A>C	p.Tyr461Ser	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>C	p.Tyr461Ser	missense_variant	Exon 15 of 28	1	NM_001142286.2	ENSP00000404092.2
SMC6	ENST00000351948.8	c.1382A>C	p.Tyr461Ser	missense_variant	Exon 14 of 27	1		ENSP00000323439.4
SMC6	ENST00000446852.5	c.1460A>C	p.Tyr487Ser	missense_variant	Exon 16 of 20	1		ENSP00000408644.1
SMC6	ENST00000402989.5	c.1382A>C	p.Tyr461Ser	missense_variant	Exon 17 of 30	2		ENSP00000384539.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459836 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 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: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1382A>C (p.Y461S) alteration is located in exon 15 (coding exon 13) of the SMC6 gene. This alteration results from a A to C substitution at nucleotide position 1382, causing the tyrosine (Y) at amino acid position 461 to be replaced by a serine (S). 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	0.065
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.69
DEOGEN2	Benign	0.032	T;T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.63	.;.;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.5	N;N;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.43	N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.79	T;T;T;T
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.22
MutPred		0.36		Loss of catalytic residue at Y461 (P = 0.035);Loss of catalytic residue at Y461 (P = 0.035);Loss of catalytic residue at Y461 (P = 0.035);.;
MVP		0.26
MPC		0.39
ClinPred		0.038	T
GERP RS		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.42

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;