9-104100202-C-T

Variant names:

• chr9-104100202-C-T
• rs200540431
• NM_006444.3:c.590C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/24 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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06691715).
• BS2: High AC in GnomAdExome4 at 72 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC2	NM_006444.3	MANE Select	c.590C>T	p.Thr197Met	missense splice_region	Exon 6 of 25	NP_006435.2	O95347-1
	SMC2	NM_001042550.2		c.590C>T	p.Thr197Met	missense splice_region	Exon 6 of 25	NP_001036015.1	O95347-1
	SMC2	NM_001042551.2		c.590C>T	p.Thr197Met	missense splice_region	Exon 6 of 25	NP_001036016.1	O95347-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC2	ENST00000374793.8	TSL:1 MANE Select	c.590C>T	p.Thr197Met	missense splice_region	Exon 6 of 25	ENSP00000363925.3	O95347-1
	SMC2	ENST00000286398.11	TSL:1	c.590C>T	p.Thr197Met	missense splice_region	Exon 6 of 25	ENSP00000286398.7	O95347-1
	SMC2	ENST00000374787.7	TSL:2	c.590C>T	p.Thr197Met	missense splice_region	Exon 6 of 25	ENSP00000363919.3	O95347-1

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

GnomAD2 exomes AF: 0.0000840 AC: 17 AN: 202342 AF XY: 0.0000359

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 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

African (AFR) AF: 0.00 AC: 0 AN: 29152

American (AMR) AF: 0.000487 AC: 14 AN: 28730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23440

East Asian (EAS) AF: 0.00 AC: 0 AN: 38432

South Asian (SAS) AF: 0.0000393 AC: 3 AN: 76398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 0.0000502 AC: 53 AN: 1056738

Other (OTH) AF: 0.0000353 AC: 2 AN: 56646

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Benign	0.11	T
Sift4G	Benign	0.098	T
Polyphen		0.66	P
Vest4		0.16
MutPred		0.33		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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

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