2-208145688-CAAAAAAAAAAAAAA-CAAAAAAAAAAA

Variant names:

• chr2-208145688-CAAA-C
• rs554918356
• NM_005210.4:c.252+83_252+85delTTT

Variant summary

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

The NM_005210.4(CRYGB):​c.252+83_252+85delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,223,772 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 0.000019 (0 hom., cov: 22)
  • Exomes 𝑓: 0.013 (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+83_252+85delTTT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8530_221+8532delAAA		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+83_252+85delTTT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8510_224+8512delAAA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8510_241+8512delAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000187 AC: 1 AN: 53464 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: 0.000676

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: 0.0135 AC: 15754 AN: 1170316 Hom.: 0 AF XY: 0.0137 AC XY: 7830 AN XY: 570644

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

African (AFR) AF: 0.0175 AC: 445 AN: 25458

American (AMR) AF: 0.0172 AC: 409 AN: 23728

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 376 AN: 16822

East Asian (EAS) AF: 0.0228 AC: 717 AN: 31388

South Asian (SAS) AF: 0.0202 AC: 1142 AN: 56518

European-Finnish (FIN) AF: 0.0280 AC: 822 AN: 29362

Middle Eastern (MID) AF: 0.0210 AC: 65 AN: 3098

European-Non Finnish (NFE) AF: 0.0117 AC: 10980 AN: 936490

Other (OTH) AF: 0.0168 AC: 798 AN: 47452

⚠️ 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: 0.0000187 AC: 1 AN: 53456 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 24914

African (AFR) AF: 0.00 AC: 0 AN: 14664

American (AMR) AF: 0.00 AC: 0 AN: 4932

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

East Asian (EAS) AF: 0.000678 AC: 1 AN: 1476

South Asian (SAS) AF: 0.00 AC: 0 AN: 1198

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 86

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26880

Other (OTH) AF: 0.00 AC: 0 AN: 676

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;