rs2228617

Variant names:

• chr7-129206487-G-C
• rs2228617
• NM_005631.5:c.1164G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-129206487-G-C
• chr7-129206487-G-T
• chr7-129206487-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005631.5(SMO):​c.1164G>C​(p.Gly388Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,613,838 control chromosomes in the GnomAD database, including 546,321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G388G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.79 (47490 hom., cov: 31)
  • Exomes 𝑓: 0.83 (498831 hom.)
• Consequence: SMO NM_005631.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.17
• Publications: 33 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
• mosaic SMO syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital hypothalamic hamartoma syndrome

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

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 7-129206487-G-C is Benign according to our data. Variant chr7-129206487-G-C is described in ClinVar as Benign. ClinVar VariationId is 403462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMO	NM_005631.5	MANE Select	c.1164G>C	p.Gly388Gly	synonymous	Exon 6 of 12	NP_005622.1	Q99835

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMO	ENST00000249373.8	TSL:1 MANE Select	c.1164G>C	p.Gly388Gly	synonymous	Exon 6 of 12	ENSP00000249373.3	Q99835
	SMO	ENST00000925242.1		c.355G>C	p.Asp119His	missense	Exon 2 of 6	ENSP00000595301.1
	SMO	ENST00000925241.1		c.1164G>C	p.Gly388Gly	synonymous	Exon 6 of 12	ENSP00000595300.1

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119557 AN: 151978 Hom.: 47468 Cov.: 31

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.956

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.819

GnomAD2 exomes AF: 0.798 AC: 200632 AN: 251400 AF XY: 0.803

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.717

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 0.768

Gnomad FIN exome AF: 0.812

Gnomad NFE exome AF: 0.841

Gnomad OTH exome AF: 0.833

GnomAD4 exome AF: 0.825 AC: 1205966 AN: 1461742 Hom.: 498831 Cov.: 57 AF XY: 0.825 AC XY: 599792 AN XY: 727158

African (AFR) AF: 0.684 AC: 22887 AN: 33476

American (AMR) AF: 0.728 AC: 32559 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 22877 AN: 26136

East Asian (EAS) AF: 0.745 AC: 29578 AN: 39698

South Asian (SAS) AF: 0.769 AC: 66297 AN: 86246

European-Finnish (FIN) AF: 0.807 AC: 43098 AN: 53404

Middle Eastern (MID) AF: 0.879 AC: 5068 AN: 5768

European-Non Finnish (NFE) AF: 0.840 AC: 934101 AN: 1111912

Other (OTH) AF: 0.820 AC: 49501 AN: 60380

GnomAD4 genome AF: 0.787 AC: 119629 AN: 152096 Hom.: 47490 Cov.: 31 AF XY: 0.783 AC XY: 58254 AN XY: 74354

African (AFR) AF: 0.691 AC: 28663 AN: 41474

American (AMR) AF: 0.745 AC: 11391 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 3037 AN: 3470

East Asian (EAS) AF: 0.754 AC: 3892 AN: 5160

South Asian (SAS) AF: 0.768 AC: 3699 AN: 4818

European-Finnish (FIN) AF: 0.824 AC: 8717 AN: 10578

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57371 AN: 67984

Other (OTH) AF: 0.816 AC: 1727 AN: 2116

Alfa AF: 0.837 Hom.: 16960

Bravo AF: 0.779

Asia WGS AF: 0.730 AC: 2538 AN: 3478

EpiCase AF: 0.850

EpiControl AF: 0.846

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital hypothalamic hamartoma syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.3
DANN	Benign	0.77
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228617; hg19: chr7-128846328; COSMIC: COSV50829466; COSMIC: COSV50829466;