chr2-17695267-G-A

Position:

• chr2-17695267-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001142286.2(SMC6):​c.2563C>T​(p.Pro855Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMC6 NM_001142286.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36289936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC6	NM_001142286.2	c.2563C>T	p.Pro855Ser	missense_variant	23/28	ENST00000448223.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC6	ENST00000448223.7	c.2563C>T	p.Pro855Ser	missense_variant	23/28	1	NM_001142286.2	P1
SMC6	ENST00000351948.8	c.2563C>T	p.Pro855Ser	missense_variant	22/27	1		P1
SMC6	ENST00000402989.5	c.2563C>T	p.Pro855Ser	missense_variant	25/30	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.2563C>T (p.P855S) alteration is located in exon 23 (coding exon 21) of the SMC6 gene. This alteration results from a C to T substitution at nucleotide position 2563, causing the proline (P) at amino acid position 855 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	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	.;.;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Benign	0.14
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.97	D;D;D
Vest4		0.29
MutPred		0.44		Loss of catalytic residue at P855 (P = 0.0057);Loss of catalytic residue at P855 (P = 0.0057);Loss of catalytic residue at P855 (P = 0.0057);
MVP		0.43
MPC		0.79
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-17876534;