Genetic Variant SMC2:p.Thr197Lys (chr9-104100202-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 17/24 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

Publications

3 publications found

Variant links:

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]

SMC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13558966).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMC2	NM_006444.3	MANE Select	c.590C>A	p.Thr197Lys	missense splice_region	Exon 6 of 25	NP_006435.2	O95347-1
SMC2	NM_001042550.2		c.590C>A	p.Thr197Lys	missense splice_region	Exon 6 of 25	NP_001036015.1	O95347-1
SMC2	NM_001042551.2		c.590C>A	p.Thr197Lys	missense splice_region	Exon 6 of 25	NP_001036016.1	O95347-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMC2	ENST00000374793.8	TSL:1 MANE Select	c.590C>A	p.Thr197Lys	missense splice_region	Exon 6 of 25	ENSP00000363925.3	O95347-1
SMC2	ENST00000286398.11	TSL:1	c.590C>A	p.Thr197Lys	missense splice_region	Exon 6 of 25	ENSP00000286398.7	O95347-1
SMC2	ENST00000374787.7	TSL:2	c.590C>A	p.Thr197Lys	missense splice_region	Exon 6 of 25	ENSP00000363919.3	O95347-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1366722

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682470

African (AFR)

AF:

0.00

AC:

AN:

29152

American (AMR)

AF:

0.00

AC:

AN:

28732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23440

East Asian (EAS)

AF:

0.00

AC:

AN:

38432

South Asian (SAS)

AF:

0.00

AC:

AN:

76398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1056740

Other (OTH)

AF:

0.00

AC:

AN:

56646

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.12

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.059

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0094

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.70

PhyloP100

2.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.14

REVEL

Benign

0.15

Sift

Benign

0.71

Sift4G

Benign

1.0

Polyphen

0.0080

Vest4

0.45

MutPred

0.37

Gain of ubiquitination at T197 (P = 0.0211)

MVP

0.30

MPC

0.18

ClinPred

0.88

GERP RS

4.9

Varity_R

0.30

gMVP

0.77

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over