9-104102017-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_006444.3(SMC2):​c.694C>T​(p.Arg232Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,458,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SMC2
NM_006444.3 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.77
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.836
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMC2NM_006444.3 linkc.694C>T p.Arg232Cys missense_variant Exon 8 of 25 ENST00000374793.8 NP_006435.2 O95347-1A0A024R158Q05BV1Q7Z2X1Q05D74

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMC2ENST00000374793.8 linkc.694C>T p.Arg232Cys missense_variant Exon 8 of 25 1 NM_006444.3 ENSP00000363925.3 O95347-1
SMC2ENST00000286398.11 linkc.694C>T p.Arg232Cys missense_variant Exon 8 of 25 1 ENSP00000286398.7 O95347-1
SMC2ENST00000374787.7 linkc.694C>T p.Arg232Cys missense_variant Exon 8 of 25 2 ENSP00000363919.3 O95347-1
SMC2ENST00000440179.5 linkc.259C>T p.Arg87Cys missense_variant Exon 6 of 6 3 ENSP00000414999.1 Q5T821

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000685
AC:
10
AN:
1458850
Hom.:
0
Cov.:
30
AF XY:
0.00000551
AC XY:
4
AN XY:
725620
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000660
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 06, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.694C>T (p.R232C) alteration is located in exon 8 (coding exon 7) of the SMC2 gene. This alteration results from a C to T substitution at nucleotide position 694, causing the arginine (R) at amino acid position 232 to be replaced by a cysteine (C). 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
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.63
D;T;D;D
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;.;.
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.84
D;D;D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Pathogenic
3.5
M;.;M;M
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-7.1
D;D;D;D
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;D;D
Vest4
0.76
MutPred
0.67
Gain of catalytic residue at L233 (P = 0.0112);.;Gain of catalytic residue at L233 (P = 0.0112);Gain of catalytic residue at L233 (P = 0.0112);
MVP
0.88
MPC
0.66
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.91
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1225165289; hg19: chr9-106864298; API