17-29250316-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005208.5(CRYBA1):c.215+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,374,546 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (170 hom., cov: 32)
  • Exomes 𝑓: 0.030 (652 hom.)
• Consequence: CRYBA1 NM_005208.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.184

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 (BayesDel_noAF=-0.86).
• BP6: Variant 17-29250316-C-T is Benign according to our data. Variant chr17-29250316-C-T is described in ClinVar as [Benign]. Clinvar id is 259671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-29250316-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBA1	NM_005208.5	c.215+16C>T		intron_variant		ENST00000225387.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBA1	ENST00000225387.8	c.215+16C>T		intron_variant		1	NM_005208.5	P1
CRYBA1	ENST00000484605.1	c.205+16C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6075 AN: 152032 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0185

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0307

GnomAD3 exomes AF: 0.0262 AC: 6590 AN: 251394 Hom.: 127 AF XY: 0.0254 AC XY: 3450 AN XY: 135878

Gnomad AFR exome AF: 0.0811

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0224

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0289

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0298 AC: 36462 AN: 1222396 Hom.: 652 Cov.: 18 AF XY: 0.0293 AC XY: 18131 AN XY: 619716

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.000207

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.0320

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0400 AC: 6090 AN: 152150 Hom.: 170 Cov.: 32 AF XY: 0.0385 AC XY: 2861 AN XY: 74386

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0187

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0299

Alfa AF: 0.0314 Hom.: 15

Bravo AF: 0.0412

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: 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 25, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.2
Dann	Benign	0.62

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: rs72819448; hg19: chr17-27577334;