Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_198569.3(ADGRG6):c.2306T>A(p.Val769Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

ADGRG6
NM_198569.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.49

Publications

7 publications found

Variant links:

Genes affected

ADGRG6 (HGNC:13841): (adhesion G protein-coupled receptor G6) This gene, which is upregulated in human umbilical vein endothelial cells, encodes a G protein-coupled receptor. Variations in this gene can affect a person's stature. Multiple transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Mar 2009]

ADGRG6 Gene-Disease associations (from GenCC):

lethal congenital contracture syndrome 9
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ADGRG6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

PP5

Variant 6-142408187-T-A is Pathogenic according to our data. Variant chr6-142408187-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 192349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198569.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADGRG6	NM_198569.3	MANE Select	c.2306T>A	p.Val769Glu	missense	Exon 16 of 25	NP_940971.2
ADGRG6	NM_001032395.3		c.2222T>A	p.Val741Glu	missense	Exon 15 of 24	NP_001027567.2
ADGRG6	NM_020455.6		c.2306T>A	p.Val769Glu	missense	Exon 16 of 26	NP_065188.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADGRG6	ENST00000367609.8	TSL:1 MANE Select	c.2306T>A	p.Val769Glu	missense	Exon 16 of 25	ENSP00000356581.3
ADGRG6	ENST00000367608.6	TSL:1	c.2222T>A	p.Val741Glu	missense	Exon 15 of 24	ENSP00000356580.2
ADGRG6	ENST00000230173.10	TSL:1	c.2306T>A	p.Val769Glu	missense	Exon 16 of 26	ENSP00000230173.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lethal congenital contracture syndrome 9 (2)

Arthrogryposis multiplex congenita (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.42

PhyloP100

6.5

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Polyphen

0.97

Vest4

0.97

MutPred

0.72

Loss of sheet (P = 0.0817)

MVP

0.81

MPC

0.66

ClinPred

1.0

GERP RS

5.4

Varity_R

0.92

gMVP

0.94

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over