9-104102427-A-C

Variant summary

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

The NM_006444.3(SMC2):c.874A>C(p.Thr292Pro) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMC2 NM_006444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

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=0.16664866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC2	NM_006444.3	c.874A>C	p.Thr292Pro	missense_variant	9/25	ENST00000374793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC2	ENST00000374793.8	c.874A>C	p.Thr292Pro	missense_variant	9/25	1	NM_006444.3	P1
SMC2	ENST00000286398.11	c.874A>C	p.Thr292Pro	missense_variant	9/25	1		P1
SMC2	ENST00000374787.7	c.874A>C	p.Thr292Pro	missense_variant	9/25	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.874A>C (p.T292P) alteration is located in exon 9 (coding exon 8) of the SMC2 gene. This alteration results from a A to C substitution at nucleotide position 874, causing the threonine (T) at amino acid position 292 to be replaced by a proline (P). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.18	T;.;.
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.36	B;B;B
Vest4		0.16
MutPred		0.53		Loss of phosphorylation at T292 (P = 0.0705);Loss of phosphorylation at T292 (P = 0.0705);Loss of phosphorylation at T292 (P = 0.0705);
MVP		0.74
MPC		0.23
ClinPred		0.24	T
GERP RS		3.2
Varity_R		0.33
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-106864708;