9-104100127-G-A

Variant names:

• chr9-104100127-G-A
• NM_006444.3:c.515G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006444.3(SMC2):​c.515G>A​(p.Arg172Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 8.03

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37651503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC2	NM_006444.3	c.515G>A	p.Arg172Lys	missense_variant	Exon 6 of 25	ENST00000374793.8	NP_006435.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC2	ENST00000374793.8	c.515G>A	p.Arg172Lys	missense_variant	Exon 6 of 25	1	NM_006444.3	ENSP00000363925.3
SMC2	ENST00000286398.11	c.515G>A	p.Arg172Lys	missense_variant	Exon 6 of 25	1		ENSP00000286398.7
SMC2	ENST00000374787.7	c.515G>A	p.Arg172Lys	missense_variant	Exon 6 of 25	2		ENSP00000363919.3
SMC2	ENST00000440179.5	c.80G>A	p.Arg27Lys	missense_variant	Exon 4 of 6	3		ENSP00000414999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.515G>A (p.R172K) alteration is located in exon 6 (coding exon 5) of the SMC2 gene. This alteration results from a G to A substitution at nucleotide position 515, causing the arginine (R) at amino acid position 172 to be replaced by a lysine (K). 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	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T;.;.
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L;.;L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.52	P;.;P;P
Vest4		0.21
MutPred		0.44		Gain of ubiquitination at R172 (P = 0.0082);.;Gain of ubiquitination at R172 (P = 0.0082);Gain of ubiquitination at R172 (P = 0.0082);
MVP		0.41
MPC		0.15
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.43
gMVP		0.79

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: chr9-106862408;