rs121908462

Variant names:

• chr16-57651247-C-G
• rs121908462
• NM_201525.4:c.112C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-57651247-C-G
• chr16-57651247-C-T
• chr16-57651247-C-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001290142.2(ADGRG1):​c.110+2C>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADGRG1 NM_001290142.2 splice_donor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.106
• Publications: 0 publications found

Genes affected

ADGRG1 (HGNC:4512): (adhesion G protein-coupled receptor G1) This gene encodes a member of the G protein-coupled receptor family and regulates brain cortical patterning. The encoded protein binds specifically to transglutaminase 2, a component of tissue and tumor stroma implicated as an inhibitor of tumor progression. Mutations in this gene are associated with a brain malformation known as bilateral frontoparietal polymicrogyria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ADGRG1 Gene-Disease associations (from GenCC):

• bilateral frontoparietal polymicrogyria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.8, offset of -46, new splice context is: cagGTgccc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290142.2. 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
	ADGRG1	NM_201525.4	MANE Select	c.112C>G	p.Arg38Gly	missense	Exon 3 of 14	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.112C>G	p.Arg38Gly	missense	Exon 4 of 15	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.112C>G	p.Arg38Gly	missense	Exon 4 of 15	NP_001357357.1	Q9Y653-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.112C>G	p.Arg38Gly	missense	Exon 3 of 14	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.112C>G	p.Arg38Gly	missense	Exon 4 of 15	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.112C>G	p.Arg38Gly	missense	Exon 4 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Benign	0.81
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.62	D
PhyloP100		0.11
PROVEAN	Uncertain	-4.0	D
MVP		0.97
ClinPred		0.96	D
GERP RS		0.55
Varity_R		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121908462; hg19: chr16-57685159;