2-208124234-T-C

Variant names:

• chr2-208124234-T-C
• rs61731517
• NM_006891.4:c.130A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.34
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• cataract 4 multiple types

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerulean cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• coralliform cataract

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000295187 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 VariationId is 333875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006891.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGD	NM_006891.4	MANE Select	c.130A>G	p.Met44Val	missense	Exon 2 of 3	NP_008822.2
	LOC100507443	NR_038437.1		n.97+5009T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGD	ENST00000264376.5	TSL:1 MANE Select	c.130A>G	p.Met44Val	missense	Exon 2 of 3	ENSP00000264376.4
	ENSG00000295187	ENST00000728538.1		n.100+5009T>C		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.117+5009T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1239 AN: 152162 Hom.: 3 Cov.: 33

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

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.: 67 Cov.: 30 AF XY: 0.00795 AC XY: 5766 AN XY: 725550

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: 41 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: 49 AN: 5262

European-Non Finnish (NFE) AF: 0.00819 AC: 9099 AN: 1110948

Other (OTH) AF: 0.00861 AC: 518 AN: 60158

GnomAD4 genome AF: 0.00816 AC: 1242 AN: 152280 Hom.: 3 Cov.: 33 AF XY: 0.00823 AC XY: 613 AN XY: 74462

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: 99 AN: 3472

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5178

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.00810 AC: 86 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00850 AC: 578 AN: 67992

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00601 Hom.: 2

Bravo AF: 0.00781

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00519 AC: 20

ExAC AF: 0.00770 AC: 931

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aculeiform cataract (1)
-	-	1	Cataract 4 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Benign	0.37	T
Sift4G	Benign	1.0	T
Polyphen		0.063	B
Vest4		0.15
MVP		0.65
MPC		0.31
ClinPred		0.016	T
GERP RS		4.3
PromoterAI		-0.025	Neutral
Varity_R		0.68
gMVP		0.62
Mutation Taster		=82/18	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: rs61731517; hg19: chr2-208988958; COSMIC: COSV52204710; COSMIC: COSV52204710;