9-104101961-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006444.3(SMC2):c.638A>G(p.Glu213Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,537,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: SMC2 NM_006444.3 missense, splice_region
• Scores: Splicing: ADA: 0.9351
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC2	NM_006444.3	c.638A>G	p.Glu213Gly	missense_variant, splice_region_variant	8/25	ENST00000374793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC2	ENST00000374793.8	c.638A>G	p.Glu213Gly	missense_variant, splice_region_variant	8/25	1	NM_006444.3	P1
SMC2	ENST00000286398.11	c.638A>G	p.Glu213Gly	missense_variant, splice_region_variant	8/25	1		P1
SMC2	ENST00000374787.7	c.638A>G	p.Glu213Gly	missense_variant, splice_region_variant	8/25	2		P1
SMC2	ENST00000440179.5	c.203A>G	p.Glu68Gly	missense_variant, splice_region_variant	6/6	3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000457 AC: 10 AN: 218674 Hom.: 0 AF XY: 0.0000671 AC XY: 8 AN XY: 119256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000672

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000455 AC: 63 AN: 1385618 Hom.: 0 Cov.: 23 AF XY: 0.0000378 AC XY: 26 AN XY: 688320

Gnomad4 AFR exome AF: 0.0000328

Gnomad4 AMR exome AF: 0.0000883

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: 0.0000525

Gnomad4 OTH exome AF: 0.0000524

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 151962 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74212

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000412 AC: 5

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

Jul 14, 2023

The c.638A>G (p.E213G) alteration is located in exon 8 (coding exon 7) of the SMC2 gene. This alteration results from a A to G substitution at nucleotide position 638, causing the glutamic acid (E) at amino acid position 213 to be replaced by a glycine (G). 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	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;T;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;.;.
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.4	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.61
MutPred		0.55		Loss of stability (P = 0.031);.;Loss of stability (P = 0.031);Loss of stability (P = 0.031);
MVP		0.91
MPC		0.60
ClinPred		0.95	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.010		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: rs567910817; hg19: chr9-106864242;