chr2-208121661-A-G

Variant names:

• chr2-208121661-A-G
• rs2305429
• NM_006891.4:c.*12T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006891.4(CRYGD):​c.*12T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 1,611,340 control chromosomes in the GnomAD database, including 693,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63886 hom., cov: 32)
  • Exomes 𝑓: 0.93 (629838 hom.)
• Consequence: CRYGD NM_006891.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.256

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]

LOC100507443 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-208121661-A-G is Benign according to our data. Variant chr2-208121661-A-G is described in ClinVar as [Benign]. Clinvar id is 260059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208121661-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGD	NM_006891.4	c.*12T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000264376.5	NP_008822.2
LOC100507443	NR_038437.1	n.97+2436A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376	c.*12T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_006891.4	ENSP00000264376.4

Frequencies

GnomAD3 genomes AF: 0.913 AC: 138812 AN: 152122 Hom.: 63830 Cov.: 32

Gnomad AFR AF: 0.919

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.798

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.850

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.900

GnomAD3 exomes AF: 0.877 AC: 218860 AN: 249596 Hom.: 97501 AF XY: 0.880 AC XY: 118893 AN XY: 135088

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.922

Gnomad EAS exome AF: 0.578

Gnomad SAS exome AF: 0.815

Gnomad FIN exome AF: 0.954

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.926 AC: 1350908 AN: 1459100 Hom.: 629838 Cov.: 47 AF XY: 0.924 AC XY: 670029 AN XY: 725460

Gnomad4 AFR exome AF: 0.917

Gnomad4 AMR exome AF: 0.786

Gnomad4 ASJ exome AF: 0.920

Gnomad4 EAS exome AF: 0.557

Gnomad4 SAS exome AF: 0.824

Gnomad4 FIN exome AF: 0.953

Gnomad4 NFE exome AF: 0.953

Gnomad4 OTH exome AF: 0.908

GnomAD4 genome AF: 0.913 AC: 138930 AN: 152240 Hom.: 63886 Cov.: 32 AF XY: 0.908 AC XY: 67548 AN XY: 74410

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.838

Gnomad4 ASJ AF: 0.918

Gnomad4 EAS AF: 0.591

Gnomad4 SAS AF: 0.799

Gnomad4 FIN AF: 0.954

Gnomad4 NFE AF: 0.951

Gnomad4 OTH AF: 0.897

Alfa AF: 0.935 Hom.: 61857

Bravo AF: 0.905

Asia WGS AF: 0.668 AC: 2323 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 4 multiple types Benign:2

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.5
DANN	Benign	0.57

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

Other links and lift over

dbSNP: rs2305429; hg19: chr2-208986385;