3-186538927-C-T

Position:

• chr3-186538927-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017541.4(CRYGS):​c.306G>A​(p.Gly102Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,614,038 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: CRYGS NM_017541.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.22

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-186538927-C-T is Benign according to our data. Variant chr3-186538927-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1207340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-186538927-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (261/152206) while in subpopulation NFE AF= 0.00293 (199/68006). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 261 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGS	NM_017541.4	c.306G>A	p.Gly102Gly	synonymous_variant	3/3	ENST00000307944.6	NP_060011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGS	ENST00000307944.6	c.306G>A	p.Gly102Gly	synonymous_variant	3/3	1	NM_017541.4	ENSP00000312099.5
CRYGS	ENST00000460288.1	n.1208G>A		non_coding_transcript_exon_variant	2/2	1
CRYGS	ENST00000392499.6	c.306G>A	p.Gly102Gly	synonymous_variant	4/4	2		ENSP00000376287.2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00184 AC: 463 AN: 251234 Hom.: 0 AF XY: 0.00186 AC XY: 252 AN XY: 135784

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00243 AC: 3551 AN: 1461832 Hom.: 5 Cov.: 31 AF XY: 0.00243 AC XY: 1767 AN XY: 727220

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74400

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00176

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	- -

Cataract 20 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.4
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114186269; hg19: chr3-186256716;