2-208145688-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr2-208145688-C-CAAAAAAAA
• rs554918356
• NM_005210.4:c.252+78_252+85dupTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005210.4(CRYGB):​c.252+78_252+85dupTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000561 in 53,462 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., cov: 22)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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+78_252+85dupTTTTTTTT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8525_221+8532dupAAAAAAAA		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+86insTTTTTTTT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8509_224+8510insAAAAAAAA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8509_241+8510insAAAAAAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000561 AC: 3 AN: 53462 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000112

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.12e-7 AC: 1 AN: 1231196 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 600846

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

African (AFR) AF: 0.00 AC: 0 AN: 26856

American (AMR) AF: 0.00 AC: 0 AN: 25676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17846

East Asian (EAS) AF: 0.00 AC: 0 AN: 33468

South Asian (SAS) AF: 0.00 AC: 0 AN: 61106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3282

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 981944

Other (OTH) AF: 0.00 AC: 0 AN: 50100

⚠️ 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: 0.0000561 AC: 3 AN: 53462 Hom.: 0 Cov.: 22 AF XY: 0.000120 AC XY: 3 AN XY: 24918

African (AFR) AF: 0.00 AC: 0 AN: 14650

American (AMR) AF: 0.00 AC: 0 AN: 4934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1368

East Asian (EAS) AF: 0.00 AC: 0 AN: 1480

South Asian (SAS) AF: 0.00 AC: 0 AN: 1208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 92

European-Non Finnish (NFE) AF: 0.000112 AC: 3 AN: 26886

Other (OTH) AF: 0.00 AC: 0 AN: 670

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.49

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;