9-104102126-C-T

Variant names:

• chr9-104102126-C-T
• rs1564072726
• NM_006444.3:c.803C>T

Variant summary

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

The NM_006444.3(SMC2):​c.803C>T​(p.Ser268Phe) 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. 15/21 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: 1.18

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=0.14466843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC2	NM_006444.3	c.803C>T	p.Ser268Phe	missense_variant	Exon 8 of 25	ENST00000374793.8	NP_006435.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC2	ENST00000374793.8	c.803C>T	p.Ser268Phe	missense_variant	Exon 8 of 25	1	NM_006444.3	ENSP00000363925.3
SMC2	ENST00000286398.11	c.803C>T	p.Ser268Phe	missense_variant	Exon 8 of 25	1		ENSP00000286398.7
SMC2	ENST00000374787.7	c.803C>T	p.Ser268Phe	missense_variant	Exon 8 of 25	2		ENSP00000363919.3
SMC2	ENST00000440179.5	c.368C>T	p.Ser123Phe	missense_variant	Exon 6 of 6	3		ENSP00000414999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803C>T (p.S268F) 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 803, causing the serine (S) at amino acid position 268 to be replaced by a phenylalanine (F). 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	Benign	0.16
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Uncertain	0.42	T;T;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.74	T;T;.;.
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L;.;L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.20	T;D;T;T
Sift4G	Uncertain	0.049	D;D;D;D
Polyphen		0.014	B;.;B;B
Vest4		0.29
MutPred		0.44		Loss of phosphorylation at S268 (P = 0.0244);.;Loss of phosphorylation at S268 (P = 0.0244);Loss of phosphorylation at S268 (P = 0.0244);
MVP		0.46
MPC		0.14
ClinPred		0.29	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs1564072726; hg19: chr9-106864407; COSMIC: COSV105140870;