9-104096272-A-C

Variant summary

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

The NM_006444.3(SMC2):c.293A>C(p.His98Pro) 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: 6.22

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.293A>C	p.His98Pro	missense_variant	3/25	ENST00000374793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC2	ENST00000374793.8	c.293A>C	p.His98Pro	missense_variant	3/25	1	NM_006444.3	P1
SMC2	ENST00000286398.11	c.293A>C	p.His98Pro	missense_variant	3/25	1		P1
SMC2	ENST00000374787.7	c.293A>C	p.His98Pro	missense_variant	3/25	2		P1
SMC2	ENST00000440179.5	c.-118+1824A>C		intron_variant		3

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

Feb 07, 2023

The c.293A>C (p.H98P) alteration is located in exon 3 (coding exon 2) of the SMC2 gene. This alteration results from a A to C substitution at nucleotide position 293, causing the histidine (H) at amino acid position 98 to be replaced by a proline (P). 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;.;.
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.78	P;P;P
Vest4		0.65
MutPred		0.59		Loss of catalytic residue at D99 (P = 0.0235);Loss of catalytic residue at D99 (P = 0.0235);Loss of catalytic residue at D99 (P = 0.0235);
MVP		0.66
MPC		0.37
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.91

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: chr9-106858553;