chr2-208124234-T-C

Position:

chr2-208124234-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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:

LOC100507443 (HGNC:):

LOC100507443 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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, 3 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1242 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYGD	NM_006891.4 linkuse as main transcript	c.130A>G	p.Met44Val	missense_variant	2/3	ENST00000264376.5
LOC100507443	NR_038437.1 linkuse as main transcript	n.97+5009T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYGD	ENST00000264376.5 linkuse as main transcript	c.130A>G	p.Met44Val	missense_variant	2/3	1	NM_006891.4	P1

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

GnomAD3 exomes

AF:

0.00774

AC:

1871

AN:

241866

Hom.:

AF XY:

0.00789

AC XY:

1044

AN XY:

132392

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 SAS exome

AF:

0.00515

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

Gnomad4 AFR exome

AF:

0.00556

Gnomad4 AMR exome

AF:

0.00639

Gnomad4 ASJ exome

AF:

0.0237

Gnomad4 EAS exome

AF:

0.00103

Gnomad4 SAS exome

AF:

0.00506

Gnomad4 FIN exome

AF:

0.00740

Gnomad4 NFE exome

AF:

0.00819

Gnomad4 OTH exome

AF:

0.00861

GnomAD4 genome

AF:

0.00816

AC:

1242

AN:

152280

Hom.:

Cov.:

AF XY:

0.00823

AC XY:

613

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00633

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.0285

Gnomad4 EAS

AF:

0.00290

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00810

Gnomad4 NFE

AF:

0.00850

Gnomad4 OTH

AF:

0.00899

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	This variant is associated with the following publications: (PMID: 21031021) -

Cataract 4 multiple types

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

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

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

MutationTaster

Benign

1.0

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

Varity_R

0.68

gMVP

0.62

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over