2-208124234-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_006891.4(CRYGD):c.130A>G(p.Met44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,610,854 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0080 ( 67 hom. )

Consequence

CRYGD
NM_006891.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.34

Variant links:

Genes affected

CRYGD (HGNC:2411): (crystallin gamma D) 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. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are tandemly organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. [provided by RefSeq, Jul 2008]

CRYGD links:

ENSG00000295187 (HGNC:):

ENSG00000295187 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006891.4

BP4

Computational evidence support a benign effect (MetaRNN=0.00966838).

BP6

Variant 2-208124234-T-C is Benign according to our data. Variant chr2-208124234-T-C is described in ClinVar as [Benign]. Clinvar id is 333875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208124234-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00816 (1242/152280) while in subpopulation AMR AF = 0.0101 (155/15312). AF 95% confidence interval is 0.00882. There are 3 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1242 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGD	NM_006891.4 link	c.130A>G	p.Met44Val	missense_variant	Exon 2 of 3	ENST00000264376.5	NP_008822.2	P07320A0A140CTX7
LOC100507443	NR_038437.1 link	n.97+5009T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5 link	c.130A>G	p.Met44Val	missense_variant	Exon 2 of 3	1	NM_006891.4	ENSP00000264376.4		P07320

Frequencies

GnomAD3 genomes

AF:

0.00814

AC:

1239

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00635

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00850

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00774

AC:

1871

AN:

241866

AF XY:

0.00789

show subpopulations

Gnomad AFR exome

AF:

0.00441

Gnomad AMR exome

AF:

0.00595

Gnomad ASJ exome

AF:

0.0251

Gnomad EAS exome

AF:

0.00156

Gnomad FIN exome

AF:

0.00710

Gnomad NFE exome

AF:

0.00897

Gnomad OTH exome

AF:

0.00865

GnomAD4 exome

AF:

0.00797

AC:

11620

AN:

1458574

Hom.:

Cov.:

AF XY:

0.00795

AC XY:

5766

AN XY:

725550

show subpopulations

African (AFR)

AF:

0.00556

AC:

186

AN:

33434

American (AMR)

AF:

0.00639

AC:

285

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.0237

AC:

619

AN:

26098

East Asian (EAS)

AF:

0.00103

AC:

AN:

39654

South Asian (SAS)

AF:

0.00506

AC:

436

AN:

86152

European-Finnish (FIN)

AF:

0.00740

AC:

387

AN:

52274

Middle Eastern (MID)

AF:

0.00931

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

0.00819

AC:

9099

AN:

1110948

Other (OTH)

AF:

0.00861

AC:

518

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

618

1236

1854

2472

3090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00816

AC:

1242

AN:

152280

Hom.:

Cov.:

AF XY:

0.00823

AC XY:

613

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00633

AC:

263

AN:

41566

American (AMR)

AF:

0.0101

AC:

155

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3472

East Asian (EAS)

AF:

0.00290

AC:

AN:

5178

South Asian (SAS)

AF:

0.00456

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00810

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00850

AC:

578

AN:

67992

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00601

Hom.:

Bravo

AF:

0.00781

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00519

AC:

ExAC

AF:

0.00770

AC:

931

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 16, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21031021) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cataract 4 multiple types

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aculeiform cataract

Benign:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.87

MetaRNN

Benign

0.0097

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.55

PhyloP100

1.3

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

REVEL

Benign

0.14

Sift

Benign

0.37

Sift4G

Benign

1.0

Polyphen

0.063

Vest4

0.15

MVP

0.65

MPC

0.31

ClinPred

0.016

GERP RS

4.3

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.68

gMVP

0.62

Mutation Taster

=82/18

polymorphism

(source)

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

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2-208124234-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over