9-104102017-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_006444.3(SMC2):c.694C>T(p.Arg232Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,458,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SMC2 NM_006444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

Genes affected

SMC2 (HGNC:14011): (structural maintenance of chromosomes 2) Predicted to enable ATP binding activity; chromatin binding activity; and single-stranded DNA binding activity. Involved in mitotic chromosome condensation. Located in condensed chromosome; cytoplasm; and nuclear lumen. Part of condensin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC2	NM_006444.3	c.694C>T	p.Arg232Cys	missense_variant	8/25	ENST00000374793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC2	ENST00000374793.8	c.694C>T	p.Arg232Cys	missense_variant	8/25	1	NM_006444.3	P1
SMC2	ENST00000286398.11	c.694C>T	p.Arg232Cys	missense_variant	8/25	1		P1
SMC2	ENST00000374787.7	c.694C>T	p.Arg232Cys	missense_variant	8/25	2		P1
SMC2	ENST00000440179.5	c.259C>T	p.Arg87Cys	missense_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1458850 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725620

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

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

Apr 06, 2023

The c.694C>T (p.R232C) alteration is located in exon 8 (coding exon 7) of the SMC2 gene. This alteration results from a C to T substitution at nucleotide position 694, causing the arginine (R) at amino acid position 232 to be replaced by a cysteine (C). 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	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;T;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.5	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.1	D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.76
MutPred		0.67		Gain of catalytic residue at L233 (P = 0.0112);.;Gain of catalytic residue at L233 (P = 0.0112);Gain of catalytic residue at L233 (P = 0.0112);
MVP		0.88
MPC		0.66
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1225165289; hg19: chr9-106864298;