chr6-73425331-T-C

Variant names:

• chr6-73425331-T-C
• NM_138441.3:c.1465A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138441.3(CGAS):​c.1465A>G​(p.Asn489Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CGAS NM_138441.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.11

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGAS	NM_138441.3	c.1465A>G	p.Asn489Asp	missense_variant	Exon 5 of 5	ENST00000370315.4	NP_612450.2
CGAS	NM_001410911.1	c.1332+133A>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.1465A>G	p.Asn489Asp	missense_variant	Exon 5 of 5	1	NM_138441.3	ENSP00000359339.3
CGAS	ENST00000370318.5	c.1332+133A>G		intron_variant	Intron 5 of 5	1		ENSP00000359342.1
CGAS	ENST00000680833.1	c.1332+133A>G		intron_variant	Intron 5 of 5			ENSP00000506638.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458412 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.64		Loss of helix (P = 0.0558);
MVP		0.32
MPC		1.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr6-74135054;