2-208145688-CAAAAAAAAAAAAAA-CAAAAAAAAAA

Variant names:

• chr2-208145688-CAAAA-C
• rs554918356
• NM_005210.4:c.252+82_252+85delTTTT

Variant summary

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

The NM_005210.4(CRYGB):​c.252+82_252+85delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,258,348 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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: 0.0044 (0 hom.)
• Consequence: CRYGB NM_005210.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• 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 0 ACMG points.

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+82_252+85delTTTT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8529_221+8532delAAAA		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+82_252+85delTTTT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8510_224+8513delAAAA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8510_241+8513delAAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000561 AC: 3 AN: 53464 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000676

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00442 AC: 5320 AN: 1204884 Hom.: 0 AF XY: 0.00456 AC XY: 2678 AN XY: 587736

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

African (AFR) AF: 0.00438 AC: 115 AN: 26284

American (AMR) AF: 0.00630 AC: 157 AN: 24934

Ashkenazi Jewish (ASJ) AF: 0.00862 AC: 150 AN: 17406

East Asian (EAS) AF: 0.00811 AC: 263 AN: 32422

South Asian (SAS) AF: 0.00663 AC: 391 AN: 59018

European-Finnish (FIN) AF: 0.0118 AC: 354 AN: 30046

Middle Eastern (MID) AF: 0.00625 AC: 20 AN: 3200

European-Non Finnish (NFE) AF: 0.00371 AC: 3575 AN: 962712

Other (OTH) AF: 0.00604 AC: 295 AN: 48862

⚠️ 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: 53464 Hom.: 0 Cov.: 22 AF XY: 0.0000401 AC XY: 1 AN XY: 24916

African (AFR) AF: 0.0000683 AC: 1 AN: 14650

American (AMR) AF: 0.000203 AC: 1 AN: 4934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1370

East Asian (EAS) AF: 0.000676 AC: 1 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: 0.00 AC: 0 AN: 26886

Other (OTH) AF: 0.00 AC: 0 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		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;