rs2290177

Variant names:

• chr16-57661692-C-T
• rs2290177
• NM_201525.4:c.1665-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201525.4(ADGRG1):​c.1665-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,611,276 control chromosomes in the GnomAD database, including 40,395 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3874 hom., cov: 33)
  • Exomes 𝑓: 0.22 (36521 hom.)
• Consequence: ADGRG1 NM_201525.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001573
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.43
• Publications: 9 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

ENSG00000306939 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-57661692-C-T is Benign according to our data. Variant chr16-57661692-C-T is described in ClinVar as Benign. ClinVar VariationId is 158624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201525.4. 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.1665-5C>T		splice_region intron	N/A	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.1683-5C>T		splice_region intron	N/A	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.1683-5C>T		splice_region intron	N/A	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.1665-5C>T		splice_region intron	N/A	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.1683-5C>T		splice_region intron	N/A	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.1665-5C>T		splice_region intron	N/A	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32591 AN: 152074 Hom.: 3868 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.231

GnomAD2 exomes AF: 0.256 AC: 61999 AN: 242228 AF XY: 0.248

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.496

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.215 AC: 313739 AN: 1459084 Hom.: 36521 Cov.: 36 AF XY: 0.215 AC XY: 155818 AN XY: 725834

African (AFR) AF: 0.167 AC: 5584 AN: 33414

American (AMR) AF: 0.402 AC: 17765 AN: 44212

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5372 AN: 26078

East Asian (EAS) AF: 0.474 AC: 18771 AN: 39626

South Asian (SAS) AF: 0.218 AC: 18729 AN: 86088

European-Finnish (FIN) AF: 0.209 AC: 11061 AN: 53042

Middle Eastern (MID) AF: 0.224 AC: 1281 AN: 5714

European-Non Finnish (NFE) AF: 0.200 AC: 221955 AN: 1110636

Other (OTH) AF: 0.219 AC: 13221 AN: 60274

GnomAD4 genome AF: 0.214 AC: 32618 AN: 152192 Hom.: 3874 Cov.: 33 AF XY: 0.220 AC XY: 16365 AN XY: 74384

African (AFR) AF: 0.162 AC: 6735 AN: 41526

American (AMR) AF: 0.321 AC: 4914 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 703 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2518 AN: 5180

South Asian (SAS) AF: 0.222 AC: 1070 AN: 4820

European-Finnish (FIN) AF: 0.211 AC: 2236 AN: 10580

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13662 AN: 68012

Other (OTH) AF: 0.229 AC: 485 AN: 2114

Alfa AF: 0.212 Hom.: 5393

Bravo AF: 0.225

Asia WGS AF: 0.323 AC: 1122 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Bilateral frontoparietal polymicrogyria (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.65
DANN	Benign	0.75
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.012
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: rs2290177; hg19: chr16-57695604; COSMIC: COSV65635348; COSMIC: COSV65635348;