NM_005210.4:c.175C>T

Variant names:

• chr2-208145851-G-A
• rs76323117
• NM_005210.4:c.175C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005210.4(CRYGB):​c.175C>T​(p.Arg59Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,102 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00072 (9 hom.)
• Consequence: CRYGB NM_005210.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.03
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012019426).
• BP6: Variant 2-208145851-G-A is Benign according to our data. Variant chr2-208145851-G-A is described in ClinVar as Benign. ClinVar VariationId is 474170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0069 (1050/152234) while in subpopulation AFR AF = 0.0242 (1006/41538). AF 95% confidence interval is 0.023. There are 14 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1050 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.175C>T	p.Arg59Trp	missense	Exon 2 of 3	NP_005201.2	P07316
	LOC100507443	NR_038437.1		n.221+8672G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGB	ENST00000260988.5	TSL:1 MANE Select	c.175C>T	p.Arg59Trp	missense	Exon 2 of 3	ENSP00000260988.4	P07316
	ENSG00000295187	ENST00000728538.1		n.224+8672G>A		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.241+8672G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00690 AC: 1050 AN: 152114 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00172 AC: 432 AN: 251334 AF XY: 0.00124

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000722 AC: 1055 AN: 1461868 Hom.: 9 Cov.: 59 AF XY: 0.000602 AC XY: 438 AN XY: 727234

African (AFR) AF: 0.0253 AC: 847 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112008

Other (OTH) AF: 0.00197 AC: 119 AN: 60396

GnomAD4 genome AF: 0.00690 AC: 1050 AN: 152234 Hom.: 14 Cov.: 31 AF XY: 0.00708 AC XY: 527 AN XY: 74428

African (AFR) AF: 0.0242 AC: 1006 AN: 41538

American (AMR) AF: 0.00190 AC: 29 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68012

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00175 Hom.: 4

Bravo AF: 0.00756

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cataract 39 multiple types (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.071
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.0
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.41
Sift	Benign	0.16	T
Sift4G	Benign	0.084	T
Polyphen		1.0	D
Vest4		0.59
MVP		0.84
MPC		0.14
ClinPred		0.053	T
GERP RS		2.9
PromoterAI		0.017	Neutral
Varity_R		0.41
gMVP		0.40
Mutation Taster		=89/11	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: rs76323117; hg19: chr2-209010575; COSMIC: COSV53680646;