9-104100202-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006444.3(SMC2):c.590C>T(p.Thr197Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00005 in 1,518,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SMC2 NM_006444.3 missense, splice_region
• Scores: Splicing: ADA: 0.6975
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06691715).
• BS2: High AC in GnomAdExome at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC2	NM_006444.3	c.590C>T	p.Thr197Met	missense_variant, splice_region_variant	6/25	ENST00000374793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC2	ENST00000374793.8	c.590C>T	p.Thr197Met	missense_variant, splice_region_variant	6/25	1	NM_006444.3	P1
SMC2	ENST00000286398.11	c.590C>T	p.Thr197Met	missense_variant, splice_region_variant	6/25	1		P1
SMC2	ENST00000374787.7	c.590C>T	p.Thr197Met	missense_variant, splice_region_variant	6/25	2		P1
SMC2	ENST00000440179.5	c.155C>T	p.Thr52Met	missense_variant, splice_region_variant	4/6	3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151984 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000840 AC: 17 AN: 202342 Hom.: 0 AF XY: 0.0000359 AC XY: 4 AN XY: 111362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000869

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000406

Gnomad OTH exome AF: 0.000432

GnomAD4 exome AF: 0.0000527 AC: 72 AN: 1366718 Hom.: 0 Cov.: 24 AF XY: 0.0000396 AC XY: 27 AN XY: 682468

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000487

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000393

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000502

Gnomad4 OTH exome AF: 0.0000353

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151984 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74224

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000756 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000165 AC: 20

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

Sep 28, 2022

The c.590C>T (p.T197M) alteration is located in exon 6 (coding exon 5) of the SMC2 gene. This alteration results from a C to T substitution at nucleotide position 590, causing the threonine (T) at amino acid position 197 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;.;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.098	T;T;T;T
Polyphen		0.66	P;.;P;P
Vest4		0.16
MutPred		0.33		Loss of phosphorylation at T197 (P = 0.0823);.;Loss of phosphorylation at T197 (P = 0.0823);Loss of phosphorylation at T197 (P = 0.0823);
MVP		0.33
MPC		0.22
ClinPred		0.054	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.70
dbscSNV1_RF	Benign	0.45
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

LitVar

Other links and lift over

dbSNP: rs200540431; hg19: chr9-106862483; COSMIC: COSV53964934;