2-208145688-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAA

Variant names:

• chr2-208145688-C-CA
• rs554918356
• NM_005210.4:c.252+85dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005210.4(CRYGB):​c.252+85dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 52,436 control chromosomes in the GnomAD database, including 73 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.051 (73 hom., cov: 22)
  • Exomes 𝑓: 0.091 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYGB NM_005210.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.489
• Publications: 0 publications found

Genes affected

CRYGB (HGNC:2409): (crystallin gamma B) 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]

CRYGB Gene-Disease associations (from GenCC):

• early-onset anterior polar cataract

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cataract 39 multiple types

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ENSG00000295187 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-208145688-C-CA is Benign according to our data. Variant chr2-208145688-C-CA is described in ClinVar as Benign. ClinVar VariationId is 1263173.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0746 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005210.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGB	NM_005210.4	MANE Select	c.252+85dupT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8532dupA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGB	ENST00000260988.5	TSL:1 MANE Select	c.252+85_252+86insT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8509_224+8510insA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8509_241+8510insA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 2676 AN: 52444 Hom.: 73 Cov.: 22

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0203

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.00832

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0109

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0514

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0908 AC: 108177 AN: 1191546 Hom.: 1 AF XY: 0.0890 AC XY: 51795 AN XY: 581688

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0852 AC: 2211 AN: 25958

American (AMR) AF: 0.0479 AC: 1205 AN: 25152

Ashkenazi Jewish (ASJ) AF: 0.0786 AC: 1366 AN: 17374

East Asian (EAS) AF: 0.0933 AC: 3042 AN: 32594

South Asian (SAS) AF: 0.0774 AC: 4590 AN: 59322

European-Finnish (FIN) AF: 0.0703 AC: 2140 AN: 30428

Middle Eastern (MID) AF: 0.0802 AC: 254 AN: 3166

European-Non Finnish (NFE) AF: 0.0938 AC: 88975 AN: 948910

Other (OTH) AF: 0.0903 AC: 4394 AN: 48642

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0510 AC: 2675 AN: 52436 Hom.: 73 Cov.: 22 AF XY: 0.0491 AC XY: 1203 AN XY: 24504

African (AFR) AF: 0.0656 AC: 950 AN: 14484

American (AMR) AF: 0.0224 AC: 110 AN: 4902

Ashkenazi Jewish (ASJ) AF: 0.0203 AC: 27 AN: 1328

East Asian (EAS) AF: 0.0870 AC: 125 AN: 1436

South Asian (SAS) AF: 0.00839 AC: 10 AN: 1192

European-Finnish (FIN) AF: 0.0300 AC: 53 AN: 1768

Middle Eastern (MID) AF: 0.0116 AC: 1 AN: 86

European-Non Finnish (NFE) AF: 0.0505 AC: 1322 AN: 26180

Other (OTH) AF: 0.0524 AC: 35 AN: 668

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.49
Mutation Taster		=100/0	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: rs554918356; hg19: chr2-209010412;