rs117757092

Positions:

• chr17-29253757-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The ENST00000225387.8(CRYBA1):​c.475G>A​(p.Gly159Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,614,048 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (10 hom.)
• Consequence: CRYBA1 ENST00000225387.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 9.54

Genes affected

CRYBA1 (HGNC:2394): (crystallin beta A1) 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. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta acidic group member, encodes two proteins (crystallin, beta A3 and crystallin, beta A1) from a single mRNA, the latter protein is 17 aa shorter than crystallin, beta A3 and is generated by use of an alternate translation initiation site. Deletion of exons 3 and 4 causes the autosomal dominant disease 'zonular cataract with sutural opacities'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0761165).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00221 (336/152278) while in subpopulation NFE AF= 0.00413 (281/68026). AF 95% confidence interval is 0.00373. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 336 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA1	NM_005208.5	c.475G>A	p.Gly159Ser	missense_variant	5/6	ENST00000225387.8	NP_005199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA1	ENST00000225387.8	c.475G>A	p.Gly159Ser	missense_variant	5/6	1	NM_005208.5	ENSP00000225387	P1
CRYBA1	ENST00000484605.1	c.*96G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	5		ENSP00000464368

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00220 AC: 554 AN: 251468 Hom.: 2 AF XY: 0.00221 AC XY: 301 AN XY: 135922

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00371 AC: 5418 AN: 1461770 Hom.: 10 Cov.: 32 AF XY: 0.00360 AC XY: 2617 AN XY: 727186

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00460

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74470

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00413

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00345 Hom.: 1

Bravo AF: 0.00220

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 10 multiple types Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -
Uncertain significance, no assertion criteria provided	research	Eye Genetics Research Group, Children's Medical Research Institute	Mar 30, 2012	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.076	T
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.60
Sift	Benign	0.18	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.86
MVP		0.92
MPC		0.96
ClinPred		0.027	T
GERP RS		5.4
Varity_R		0.42
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs117757092; hg19: chr17-27580775;