NM_006444.3:c.590C>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006444.3(SMC2):​c.590C>A​(p.Thr197Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T197M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMC2 NM_006444.3 missense, splice_region
• Scores: Splicing: ADA: 0.02272
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13558966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC2	NM_006444.3	c.590C>A	p.Thr197Lys	missense_variant, splice_region_variant	Exon 6 of 25	ENST00000374793.8	NP_006435.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC2	ENST00000374793.8	c.590C>A	p.Thr197Lys	missense_variant, splice_region_variant	Exon 6 of 25	1	NM_006444.3	ENSP00000363925.3
SMC2	ENST00000286398.11	c.590C>A	p.Thr197Lys	missense_variant, splice_region_variant	Exon 6 of 25	1		ENSP00000286398.7
SMC2	ENST00000374787.7	c.590C>A	p.Thr197Lys	missense_variant, splice_region_variant	Exon 6 of 25	2		ENSP00000363919.3
SMC2	ENST00000440179.5	c.155C>A	p.Thr52Lys	missense_variant, splice_region_variant	Exon 4 of 6	3		ENSP00000414999.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1366722 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 682470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.059
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;.;.
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.70	N;.;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.14	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.71	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0080	B;.;B;B
Vest4		0.45
MutPred		0.37		Gain of ubiquitination at T197 (P = 0.0211);.;Gain of ubiquitination at T197 (P = 0.0211);Gain of ubiquitination at T197 (P = 0.0211);
MVP		0.30
MPC		0.18
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.023
dbscSNV1_RF	Benign	0.22
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;