NM_005210.4:c.252+85delT

Variant names:

• chr2-208145688-CA-C
• rs554918356
• NM_005210.4:c.252+85delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005210.4(CRYGB):​c.252+85delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 53,560 control chromosomes in the GnomAD database, including 278 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (278 hom., cov: 22)
  • Exomes 𝑓: 0.24 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYGB NM_005210.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-208145688-CA-C is Benign according to our data. Variant chr2-208145688-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1257871.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

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+85delT		intron	N/A	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8532delA		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+85delT		intron	N/A	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8510delA		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8510delA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.232 AC: 12413 AN: 53568 Hom.: 276 Cov.: 22

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.0822

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.231

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.244 AC: 283735 AN: 1161716 Hom.: 15 AF XY: 0.240 AC XY: 136372 AN XY: 567740

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

African (AFR) AF: 0.255 AC: 6555 AN: 25712

American (AMR) AF: 0.160 AC: 4015 AN: 25144

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 3847 AN: 17138

East Asian (EAS) AF: 0.199 AC: 6412 AN: 32302

South Asian (SAS) AF: 0.190 AC: 11096 AN: 58414

European-Finnish (FIN) AF: 0.193 AC: 5854 AN: 30376

Middle Eastern (MID) AF: 0.256 AC: 806 AN: 3146

European-Non Finnish (NFE) AF: 0.253 AC: 233652 AN: 921932

Other (OTH) AF: 0.242 AC: 11498 AN: 47552

⚠️ 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: 0.232 AC: 12420 AN: 53560 Hom.: 278 Cov.: 22 AF XY: 0.227 AC XY: 5650 AN XY: 24940

African (AFR) AF: 0.274 AC: 4025 AN: 14682

American (AMR) AF: 0.238 AC: 1177 AN: 4936

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 345 AN: 1372

East Asian (EAS) AF: 0.0824 AC: 122 AN: 1480

South Asian (SAS) AF: 0.127 AC: 152 AN: 1200

European-Finnish (FIN) AF: 0.181 AC: 320 AN: 1768

Middle Eastern (MID) AF: 0.186 AC: 16 AN: 86

European-Non Finnish (NFE) AF: 0.223 AC: 6010 AN: 26954

Other (OTH) AF: 0.229 AC: 155 AN: 676

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: 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		-0.49
Mutation Taster		=100/0	polymorphism (auto)

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;