2-208145688-CAAAAAAAAAAAAAA-CAAAAAAAA

Variant names:

• chr2-208145688-CAAAAAA-C
• rs554918356
• NM_005210.4:c.252+80_252+85delTTTTTT

Variant summary

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

The NM_005210.4(CRYGB):​c.252+80_252+85delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,282,396 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: 0.00037 (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+80_252+85delTTTTTT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8527_221+8532delAAAAAA		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+80_252+85delTTTTTT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8510_224+8515delAAAAAA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8510_241+8515delAAAAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000187 AC: 1 AN: 53458 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: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000369 AC: 453 AN: 1228938 Hom.: 0 AF XY: 0.000370 AC XY: 222 AN XY: 599692

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

African (AFR) AF: 0.000149 AC: 4 AN: 26802

American (AMR) AF: 0.000313 AC: 8 AN: 25584

Ashkenazi Jewish (ASJ) AF: 0.000731 AC: 13 AN: 17788

East Asian (EAS) AF: 0.000750 AC: 25 AN: 33350

South Asian (SAS) AF: 0.000427 AC: 26 AN: 60958

European-Finnish (FIN) AF: 0.000844 AC: 26 AN: 30820

Middle Eastern (MID) AF: 0.000611 AC: 2 AN: 3274

European-Non Finnish (NFE) AF: 0.000335 AC: 328 AN: 980374

Other (OTH) AF: 0.000420 AC: 21 AN: 49988

⚠️ 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: 53458 Hom.: 0 Cov.: 22 AF XY: 0.0000401 AC XY: 1 AN XY: 24912

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

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

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

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

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

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

European-Finnish (FIN) AF: 0.000566 AC: 1 AN: 1766

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26884

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

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

Other links and lift over

dbSNP: rs554918356; hg19: chr2-209010412;