Genetic Variant SMC2:p.Ser215Leu (chr9-104101967-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_006444.3(SMC2):c.644C>T(p.Ser215Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000904 in 1,547,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S215W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

SMC2
NM_006444.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.04

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34967637).

BS2

High AC in GnomAdExome4 at 11 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMC2	NM_006444.3	MANE Select	c.644C>T	p.Ser215Leu	missense	Exon 8 of 25	NP_006435.2	O95347-1
SMC2	NM_001042550.2		c.644C>T	p.Ser215Leu	missense	Exon 8 of 25	NP_001036015.1	O95347-1
SMC2	NM_001042551.2		c.644C>T	p.Ser215Leu	missense	Exon 8 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.644C>T	p.Ser215Leu	missense	Exon 8 of 25	ENSP00000363925.3	O95347-1
SMC2	ENST00000286398.11	TSL:1	c.644C>T	p.Ser215Leu	missense	Exon 8 of 25	ENSP00000286398.7	O95347-1
SMC2	ENST00000374787.7	TSL:2	c.644C>T	p.Ser215Leu	missense	Exon 8 of 25	ENSP00000363919.3	O95347-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000226

AC:

AN:

221650

AF XY:

0.0000249

show subpopulations

Gnomad AFR exome

AF:

0.0000669

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000381

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000788

AC:

AN:

1396366

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

693308

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31038

American (AMR)

AF:

0.00

AC:

AN:

36034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24350

East Asian (EAS)

AF:

0.00

AC:

AN:

38738

South Asian (SAS)

AF:

0.00

AC:

AN:

77516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00000839

AC:

AN:

1072794

Other (OTH)

AF:

0.0000173

AC:

AN:

57694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151584

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73984

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41202

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.054

MetaRNN

Benign

0.35

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.5

PhyloP100

6.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.18

Sift

Uncertain

0.011

Sift4G

Benign

0.21

Polyphen

0.89

Vest4

0.47

MutPred

0.41

Loss of phosphorylation at S215 (P = 0.0221)

MVP

0.49

MPC

0.20

ClinPred

0.66

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.63

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over