7-129212264-G-C

Variant names:

• chr7-129212264-G-C
• rs142495470
• NM_005631.5:c.2177G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005631.5(SMO):​c.2177G>C​(p.Arg726Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R726Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.560
• Publications: 0 publications found

Genes affected

SMO (HGNC:11119): (smoothened, frizzled class receptor) The protein encoded by this gene is a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. The encoded protein tranduces signals to other proteins after activation by a hedgehog protein/patched protein complex. [provided by RefSeq, Jul 2010]

SMO Gene-Disease associations (from GenCC):

• Curry-Jones syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• congenital hypothalamic hamartoma syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, ClinGen
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000243230 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23609793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5	c.2177G>C	p.Arg726Pro	missense_variant	Exon 12 of 12	ENST00000249373.8	NP_005622.1
SMO	XM_047420759.1	c.1787G>C	p.Arg596Pro	missense_variant	Exon 13 of 13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMO	ENST00000249373.8	c.2177G>C	p.Arg726Pro	missense_variant	Exon 12 of 12	1	NM_005631.5	ENSP00000249373.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.56
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Benign	0.031	D
Sift4G	Benign	0.18	T
Vest4		0.18
ClinPred		0.33	T
GERP RS		5.4
Varity_R		0.31
gMVP		0.25
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142495470; hg19: chr7-128852105;