Variant 6-73425426-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138441.3(CGAS):c.1370G>A(p.Arg457His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CGAS
NM_138441.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.884

Variant links:

Genes affected

CGAS (HGNC:21367): (cyclic GMP-AMP synthase) Enables several functions, including 2',3'-cyclic GMP-AMP synthase activity; chromatin binding activity; and phosphatidylinositol-4,5-bisphosphate binding activity. Involved in several processes, including cellular response to exogenous dsRNA; positive regulation of intracellular signal transduction; and regulation of defense response. Located in several cellular components, including cytosol; nucleus; and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

CGAS links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055879533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CGAS	NM_138441.3 linkuse as main transcript	c.1370G>A	p.Arg457His	missense_variant	5/5	ENST00000370315.4	NP_612450.2	Q8N884-1
CGAS	NM_001410911.1 linkuse as main transcript	c.1332+38G>A		intron_variant			NP_001397840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CGAS	ENST00000370315.4 linkuse as main transcript	c.1370G>A	p.Arg457His	missense_variant	5/5	1	NM_138441.3	ENSP00000359339.3	Q8N884-1
CGAS	ENST00000370318.5 linkuse as main transcript	c.1332+38G>A		intron_variant		1		ENSP00000359342.1	Q8N884-2
CGAS	ENST00000680833.1 linkuse as main transcript	c.1332+38G>A		intron_variant				ENSP00000506638.1	A0A7P0TBQ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2022

The c.1370G>A (p.R457H) alteration is located in exon 5 (coding exon 5) of the MB21D1 gene. This alteration results from a G to A substitution at nucleotide position 1370, causing the arginine (R) at amino acid position 457 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.86

DANN

Benign

0.54

DEOGEN2

Benign

0.0063

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.37

M_CAP

Benign

0.0021

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.49

REVEL

Benign

0.018

Sift

Benign

0.54

Sift4G

Benign

0.54

Polyphen

0.0010

Vest4

0.039

MutPred

0.47

Loss of ubiquitination at K458 (P = 0.0539);

MVP

0.040

MPC

0.37

ClinPred

0.027

GERP RS

-4.1

Varity_R

0.066

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over