chr2-208145688-CAA-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_005210.4(CRYGB):​c.252+84_252+85delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,170,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 22)
  • Exomes 𝑓: 0.060 (0 hom.)
• Consequence: CRYGB NM_005210.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-208145688-CAA-C is Benign according to our data. Variant chr2-208145688-CAA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1317988.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 166 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+85delTT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8531_221+8532delAA		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+84_252+85delTT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8510_224+8511delAA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8510_241+8511delAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 166 AN: 53446 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00943

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00264

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: 0.000521

Gnomad OTH AF: 0.00149

GnomAD4 exome AF: 0.0596 AC: 66545 AN: 1117364 Hom.: 0 AF XY: 0.0599 AC XY: 32644 AN XY: 544926

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

African (AFR) AF: 0.0752 AC: 1834 AN: 24384

American (AMR) AF: 0.0660 AC: 1528 AN: 23136

Ashkenazi Jewish (ASJ) AF: 0.0800 AC: 1294 AN: 16170

East Asian (EAS) AF: 0.0693 AC: 2100 AN: 30310

South Asian (SAS) AF: 0.0669 AC: 3606 AN: 53928

European-Finnish (FIN) AF: 0.0833 AC: 2407 AN: 28912

Middle Eastern (MID) AF: 0.0721 AC: 215 AN: 2984

European-Non Finnish (NFE) AF: 0.0566 AC: 50527 AN: 892118

Other (OTH) AF: 0.0668 AC: 3034 AN: 45422

⚠️ 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: 0.00311 AC: 166 AN: 53438 Hom.: 0 Cov.: 22 AF XY: 0.00321 AC XY: 80 AN XY: 24902

African (AFR) AF: 0.00942 AC: 138 AN: 14654

American (AMR) AF: 0.00264 AC: 13 AN: 4930

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1476

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1764

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

European-Non Finnish (NFE) AF: 0.000521 AC: 14 AN: 26878

Other (OTH) AF: 0.00148 AC: 1 AN: 676

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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)		0.0		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;