9-104101967-C-G

Variant summary

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

The NM_006444.3(SMC2):c.644C>G(p.Ser215Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMC2 NM_006444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC2	NM_006444.3	c.644C>G	p.Ser215Trp	missense_variant	8/25	ENST00000374793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC2	ENST00000374793.8	c.644C>G	p.Ser215Trp	missense_variant	8/25	1	NM_006444.3	P1
SMC2	ENST00000286398.11	c.644C>G	p.Ser215Trp	missense_variant	8/25	1		P1
SMC2	ENST00000374787.7	c.644C>G	p.Ser215Trp	missense_variant	8/25	2		P1
SMC2	ENST00000440179.5	c.209C>G	p.Ser70Trp	missense_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

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

Feb 07, 2023

The c.644C>G (p.S215W) alteration is located in exon 8 (coding exon 7) of the SMC2 gene. This alteration results from a C to G substitution at nucleotide position 644, causing the serine (S) at amino acid position 215 to be replaced by a tryptophan (W). 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	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;T;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.5	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.53
MutPred		0.47		Loss of disorder (P = 0.0019);.;Loss of disorder (P = 0.0019);Loss of disorder (P = 0.0019);
MVP		0.51
MPC		0.64
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr9-106864248;