6-73425370-T-C

Variant names:

• chr6-73425370-T-C
• NM_138441.3:c.1426A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138441.3(CGAS):​c.1426A>G​(p.Arg476Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: CGAS NM_138441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22769138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGAS	NM_138441.3	c.1426A>G	p.Arg476Gly	missense_variant	Exon 5 of 5	ENST00000370315.4	NP_612450.2
CGAS	NM_001410911.1	c.1332+94A>G		intron_variant	Intron 5 of 5		NP_001397840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CGAS	ENST00000370315.4	c.1426A>G	p.Arg476Gly	missense_variant	Exon 5 of 5	1	NM_138441.3	ENSP00000359339.3
CGAS	ENST00000370318.5	c.1332+94A>G		intron_variant	Intron 5 of 5	1		ENSP00000359342.1
CGAS	ENST00000680833.1	c.1332+94A>G		intron_variant	Intron 5 of 5			ENSP00000506638.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1426A>G (p.R476G) alteration is located in exon 5 (coding exon 5) of the MB21D1 gene. This alteration results from a A to G substitution at nucleotide position 1426, causing the arginine (R) at amino acid position 476 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.035
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.049	D
Polyphen		0.80	P
Vest4		0.18
MutPred		0.58		Gain of ubiquitination at K479 (P = 0.0898);
MVP		0.26
MPC		0.79
ClinPred		0.87	D
GERP RS		3.2
Varity_R		0.74
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-74135093;