rs142631461

chr17-29249184-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005208.5(CRYBA1):c.74C>T(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,612,402 control chromosomes in the GnomAD database, including 651 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P25P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (36 hom., cov: 31)
  • Exomes 𝑓: 0.027 (615 hom.)
• Consequence: CRYBA1 NM_005208.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.18

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055909455).
• BP6: Variant 17-29249184-C-T is Benign according to our data. Variant chr17-29249184-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-29249184-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2837/152200) while in subpopulation NFE AF= 0.0298 (2028/67998). AF 95% confidence interval is 0.0287. There are 36 homozygotes in gnomad4. There are 1311 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2838 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBA1	NM_005208.5	c.74C>T	p.Pro25Leu	missense_variant	2/6	ENST00000225387.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBA1	ENST00000225387.8	c.74C>T	p.Pro25Leu	missense_variant	2/6	1	NM_005208.5	P1
CRYBA1	ENST00000484605.1	c.65C>T	p.Pro22Leu	missense_variant, NMD_transcript_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2838 AN: 152082 Hom.: 36 Cov.: 31

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0172 AC: 4326 AN: 251296 Hom.: 43 AF XY: 0.0175 AC XY: 2379 AN XY: 135852

Gnomad AFR exome AF: 0.00512

Gnomad AMR exome AF: 0.00824

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00470

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.0273

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0266 AC: 38835 AN: 1460202 Hom.: 615 Cov.: 29 AF XY: 0.0257 AC XY: 18666 AN XY: 726520

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.00870

Gnomad4 ASJ exome AF: 0.0138

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00467

Gnomad4 FIN exome AF: 0.0221

Gnomad4 NFE exome AF: 0.0314

Gnomad4 OTH exome AF: 0.0243

GnomAD4 genome AF: 0.0186 AC: 2837 AN: 152200 Hom.: 36 Cov.: 31 AF XY: 0.0176 AC XY: 1311 AN XY: 74402

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0246

Gnomad4 NFE AF: 0.0298

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0246 Hom.: 83

Bravo AF: 0.0177

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0270 AC: 232

ExAC AF: 0.0172 AC: 2088

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cataract 10 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2023

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Benign	0.83
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Uncertain	0.027	D
Sift4G	Benign	0.21	T
Polyphen		0.30	B
Vest4		0.20
MPC		0.32
ClinPred		0.022	T
GERP RS		3.7
Varity_R		0.075
gMVP		0.35

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: rs142631461; hg19: chr17-27576202;