chr3-186539595-A-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_017541.4(CRYGS):c.24T>G(p.Ile8Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I8N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CRYGS
NM_017541.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0890

Publications

0 publications found

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 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

CRYGS links:

ENSG00000294974 (HGNC:):

ENSG00000294974 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a domain Beta/gamma crystallin 'Greek key' 1 (size 38) in uniprot entity CRYGS_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_017541.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-186539596-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1098390.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.2428 (below the threshold of 3.09). Trascript score misZ: 0.85394 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 20 multiple types, early-onset lamellar cataract, early-onset sutural cataract.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGS	NM_017541.4 link	c.24T>G	p.Ile8Met	missense_variant, splice_region_variant	Exon 2 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.24T>G	p.Ile8Met	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_017541.4	ENSP00000312099.5	P22914
CRYGS	ENST00000460288.1 link	n.926T>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
CRYGS	ENST00000392499.6 link	c.24T>G	p.Ile8Met	missense_variant, splice_region_variant	Exon 3 of 4	2		ENSP00000376287.2	P22914
ENSG00000294974	ENST00000727128.1 link	n.188-13241A>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111858

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

D;D

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.56

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

-0.23

PhyloP100

0.089

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.98

D;D

Vest4

0.75

MutPred

0.83

Gain of disorder (P = 0.0091);Gain of disorder (P = 0.0091);

MVP

0.75

MPC

0.63

ClinPred

0.98

GERP RS

-11

Varity_R

0.89

gMVP

0.61

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over