rs150441905

Variant names:

• chr3-186539172-C-T
• rs150441905
• NM_017541.4:c.264+183G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017541.4(CRYGS):​c.264+183G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 152,214 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0059 (6 hom., cov: 32)
• Consequence: CRYGS NM_017541.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.346
• Publications: 0 publications found

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]

CRYGS Gene-Disease associations (from GenCC):

• cataract 20 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294974 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-186539172-C-T is Benign according to our data. Variant chr3-186539172-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1207175.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00587 (894/152214) while in subpopulation NFE AF = 0.00785 (534/68020). AF 95% confidence interval is 0.0073. There are 6 homozygotes in GnomAd4. There are 448 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 894 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017541.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGS	NM_017541.4	MANE Select	c.264+183G>A		intron	N/A	NP_060011.1	P22914

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGS	ENST00000307944.6	TSL:1 MANE Select	c.264+183G>A		intron	N/A	ENSP00000312099.5	P22914
	CRYGS	ENST00000460288.1	TSL:1	n.1166+183G>A		intron	N/A
	CRYGS	ENST00000392499.6	TSL:2	c.264+183G>A		intron	N/A	ENSP00000376287.2	P22914

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 895 AN: 152096 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00786

Gnomad OTH AF: 0.00669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152214 Hom.: 6 Cov.: 32 AF XY: 0.00602 AC XY: 448 AN XY: 74434

African (AFR) AF: 0.00137 AC: 57 AN: 41538

American (AMR) AF: 0.00556 AC: 85 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.0156 AC: 165 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00785 AC: 534 AN: 68020

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00646 Hom.: 0

Bravo AF: 0.00519

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.7
DANN	Benign	0.40
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150441905; hg19: chr3-186256961;