6-73425426-C-T

Variant names:

• chr6-73425426-C-T
• rs968744350
• NM_138441.3:c.1370G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R457C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CGAS NM_138441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.884

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 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 rank	MANE	Protein	UniProt
CGAS	NM_138441.3	c.1370G>A	p.Arg457His	missense_variant	Exon 5 of 5	ENST00000370315.4	NP_612450.2
CGAS	NM_001410911.1	c.1332+38G>A		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.1370G>A	p.Arg457His	missense_variant	Exon 5 of 5	1	NM_138441.3	ENSP00000359339.3
CGAS	ENST00000370318.5	c.1332+38G>A		intron_variant	Intron 5 of 5	1		ENSP00000359342.1
CGAS	ENST00000680833.1	c.1332+38G>A		intron_variant	Intron 5 of 5			ENSP00000506638.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

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.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.86
DANN	Benign	0.54
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.018
Sift	Benign	0.54	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.039
MutPred		0.47		Loss of ubiquitination at K458 (P = 0.0539);
MVP		0.040
MPC		0.37
ClinPred		0.027	T
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

Other links and lift over

dbSNP: rs968744350; hg19: chr6-74135149;