chr17-29249001-G-A

Position:

• chr17-29249001-G-A

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.32-141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 698,414 control chromosomes in the GnomAD database, including 6,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1386 hom., cov: 31)
  • Exomes 𝑓: 0.12 (5021 hom.)
• Consequence: CRYBA1 NM_005208.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.249

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=-0.81).
• BP6: Variant 17-29249001-G-A is Benign according to our data. Variant chr17-29249001-G-A is described in ClinVar as [Benign]. Clinvar id is 1271693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA1	NM_005208.5	c.32-141G>A		intron_variant		ENST00000225387.8	NP_005199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA1	ENST00000225387.8	c.32-141G>A		intron_variant		1	NM_005208.5	ENSP00000225387	P1
CRYBA1	ENST00000484605.1	c.22-141G>A		intron_variant, NMD_transcript_variant		5		ENSP00000464368

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19231 AN: 151888 Hom.: 1384 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0978

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.121 AC: 66323 AN: 546408 Hom.: 5021 AF XY: 0.122 AC XY: 36063 AN XY: 295054

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.0980

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0949

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.127 AC: 19250 AN: 152006 Hom.: 1386 Cov.: 31 AF XY: 0.129 AC XY: 9546 AN XY: 74286

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0977

Gnomad4 OTH AF: 0.113

Alfa AF: 0.108 Hom.: 133

Bravo AF: 0.129

Asia WGS AF: 0.222 AC: 773 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.81
CADD	Benign	0.48
DANN	Benign	0.67

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: rs8080840; hg19: chr17-27576019;