12-14806581-C-G

Variant names:

• chr12-14806581-C-G
• rs769794820
• NM_001013698.2:c.100G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001013698.2(SMCO3):​c.100G>C​(p.Asp34His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMCO3 NM_001013698.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203

Genes affected

SMCO3 (HGNC:34401): (single-pass membrane protein with coiled-coil domains 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

C12orf60 (HGNC:28726): (chromosome 12 open reading frame 60)

ENSG00000286107 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020595193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCO3	NM_001013698.2	c.100G>C	p.Asp34His	missense_variant	Exon 2 of 2	ENST00000316048.2	NP_001013720.2
C12orf60	NM_175874.4	c.-25+2830C>G		intron_variant	Intron 1 of 1	ENST00000330828.3	NP_787070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCO3	ENST00000316048.2	c.100G>C	p.Asp34His	missense_variant	Exon 2 of 2	1	NM_001013698.2	ENSP00000381895.1
C12orf60	ENST00000330828.3	c.-25+2830C>G		intron_variant	Intron 1 of 1	1	NM_175874.4	ENSP00000331691.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249430 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.7
DANN	Benign	0.65
DEOGEN2	Benign	0.00088	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.025
Sift	Benign	0.78	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.22		Gain of catalytic residue at D34 (P = 0.0185);
MVP		0.014
MPC		0.030
ClinPred		0.049	T
GERP RS		-3.0
Varity_R		0.067
gMVP		0.35

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: rs769794820; hg19: chr12-14959515;