3-186538878-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2

The NM_017541.4(CRYGS):c.355A>G(p.Met119Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CRYGS
NM_017541.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0770

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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

BP4

Computational evidence support a benign effect (MetaRNN=0.02276513).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000105 (16/152240) while in subpopulation AFR AF= 0.000337 (14/41524). AF 95% confidence interval is 0.000204. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGS	NM_017541.4 link	c.355A>G	p.Met119Val	missense_variant	Exon 3 of 3	ENST00000307944.6	NP_060011.1	P22914A0A140CTX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRYGS	ENST00000307944.6 link	c.355A>G	p.Met119Val	missense_variant	Exon 3 of 3	1	NM_017541.4	ENSP00000312099.5	P22914
CRYGS	ENST00000460288.1 link	n.1257A>G		non_coding_transcript_exon_variant	Exon 2 of 2	1
CRYGS	ENST00000392499.6 link	c.355A>G	p.Met119Val	missense_variant	Exon 4 of 4	2		ENSP00000376287.2	P22914

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251370

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000105

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.65

.;T

M_CAP

Benign

0.0080

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.99

N;N

REVEL

Benign

0.18

Sift

Benign

0.36

T;T

Sift4G

Benign

0.46

T;T

Polyphen

0.0010

B;B

Vest4

0.11

MVP

0.43

MPC

0.15

ClinPred

0.017

GERP RS

-5.7

Varity_R

0.11

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over