chr3-186539383-C-A

Variant names:

• chr3-186539383-C-A
• NM_017541.4:c.236G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_017541.4(CRYGS):​c.236G>T​(p.Arg79Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,896 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRYGS NM_017541.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70

Genes affected

CRYGS (HGNC:2417): (crystallin gamma S) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. This gene encodes a protein initially considered to be a beta-crystallin but the encoded protein is monomeric and has greater sequence similarity to other gamma-crystallins. This gene encodes the most significant gamma-crystallin in adult eye lens tissue. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Gamma-crystallin S (size 176) in uniprot entity CRYGS_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_017541.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGS	NM_017541.4	c.236G>T	p.Arg79Leu	missense_variant	Exon 2 of 3	ENST00000307944.6	NP_060011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYGS	ENST00000307944.6	c.236G>T	p.Arg79Leu	missense_variant	Exon 2 of 3	1	NM_017541.4	ENSP00000312099.5
CRYGS	ENST00000460288.1	n.1138G>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
CRYGS	ENST00000392499.6	c.236G>T	p.Arg79Leu	missense_variant	Exon 3 of 4	2		ENSP00000376287.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459896 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726248

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	.;T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.36	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.93	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.20	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.47	P;P
Vest4		0.75
MutPred		0.60		Loss of catalytic residue at R79 (P = 0.0261);Loss of catalytic residue at R79 (P = 0.0261);
MVP		0.86
MPC		0.28
ClinPred		0.62	D
GERP RS		6.2
Varity_R		0.61
gMVP		0.67

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: chr3-186257172;