2-208145688-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAA

Variant names:

• chr2-208145688-C-CAA
• rs554918356
• NM_005210.4:c.252+84_252+85dupTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005210.4(CRYGB):​c.252+84_252+85dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 1,269,200 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 22)
  • Exomes 𝑓: 0.0058 (1 hom.)
• Consequence: CRYGB NM_005210.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 260 AD gene.

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+84_252+85dupTT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8531_221+8532dupAA		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+86insTT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8509_224+8510insAA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8509_241+8510insAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00491 AC: 259 AN: 52800 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00666

Gnomad AMI AF: 0.00758

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00147

Gnomad EAS AF: 0.00546

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0109

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.00151

GnomAD4 exome AF: 0.00577 AC: 7015 AN: 1216408 Hom.: 1 AF XY: 0.00573 AC XY: 3401 AN XY: 593658

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

African (AFR) AF: 0.00842 AC: 223 AN: 26474

American (AMR) AF: 0.00435 AC: 111 AN: 25508

Ashkenazi Jewish (ASJ) AF: 0.00565 AC: 100 AN: 17692

East Asian (EAS) AF: 0.0102 AC: 336 AN: 32990

South Asian (SAS) AF: 0.00682 AC: 412 AN: 60408

European-Finnish (FIN) AF: 0.00809 AC: 248 AN: 30646

Middle Eastern (MID) AF: 0.00585 AC: 19 AN: 3246

European-Non Finnish (NFE) AF: 0.00540 AC: 5241 AN: 969978

Other (OTH) AF: 0.00657 AC: 325 AN: 49466

⚠️ 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: 0.00492 AC: 260 AN: 52792 Hom.: 1 Cov.: 22 AF XY: 0.00467 AC XY: 115 AN XY: 24612

African (AFR) AF: 0.00672 AC: 98 AN: 14584

American (AMR) AF: 0.00184 AC: 9 AN: 4900

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 2 AN: 1356

East Asian (EAS) AF: 0.00547 AC: 8 AN: 1462

South Asian (SAS) AF: 0.000839 AC: 1 AN: 1192

European-Finnish (FIN) AF: 0.00113 AC: 2 AN: 1764

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

European-Non Finnish (NFE) AF: 0.00512 AC: 135 AN: 26382

Other (OTH) AF: 0.00149 AC: 1 AN: 670

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs554918356; hg19: chr2-209010412;