3-186539366-C-T

Position:

• chr3-186539366-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_017541.4(CRYGS):​c.253G>A​(p.Ala85Thr) 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 1,459,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRYGS NM_017541.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.2515536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGS	NM_017541.4	c.253G>A	p.Ala85Thr	missense_variant	2/3	ENST00000307944.6	NP_060011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGS	ENST00000307944.6	c.253G>A	p.Ala85Thr	missense_variant	2/3	1	NM_017541.4	ENSP00000312099	P1
CRYGS	ENST00000460288.1	n.1155G>A		non_coding_transcript_exon_variant	1/2	1
CRYGS	ENST00000392499.6	c.253G>A	p.Ala85Thr	missense_variant	3/4	2		ENSP00000376287	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726246

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 20 multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2016

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CRYGS-related disease. This sequence change replaces alanine with threonine at codon 85 of the CRYGS protein (p.Ala85Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.20
Sift	Benign	0.18	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.032	B;B
Vest4		0.21
MutPred		0.38		Gain of phosphorylation at A85 (P = 0.075);Gain of phosphorylation at A85 (P = 0.075);
MVP		0.78
MPC		0.16
ClinPred		0.26	T
GERP RS		6.2
Varity_R		0.20
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs1553846926; hg19: chr3-186257155;