chr17-29249281-T-G

Position:

• chr17-29249281-T-G

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.96+75T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,047,860 control chromosomes in the GnomAD database, including 8,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1456 hom., cov: 31)
  • Exomes 𝑓: 0.12 (7354 hom.)
• Consequence: CRYBA1 NM_005208.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.158

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=-0.8).
• BP6: Variant 17-29249281-T-G is Benign according to our data. Variant chr17-29249281-T-G is described in ClinVar as [Benign]. Clinvar id is 1232029.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	UniProt
CRYBA1	NM_005208.5	c.96+75T>G		intron_variant		ENST00000225387.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBA1	ENST00000225387.8	c.96+75T>G		intron_variant		1	NM_005208.5	P1
CRYBA1	ENST00000484605.1	c.86+75T>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19755 AN: 151866 Hom.: 1454 Cov.: 31

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0977

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.116 AC: 103678 AN: 895876 Hom.: 7354 AF XY: 0.117 AC XY: 54576 AN XY: 468090

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.0958

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0956

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.130 AC: 19779 AN: 151984 Hom.: 1456 Cov.: 31 AF XY: 0.132 AC XY: 9787 AN XY: 74300

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0977

Gnomad4 OTH AF: 0.113

Alfa AF: 0.0988 Hom.: 1396

Bravo AF: 0.132

Asia WGS AF: 0.228 AC: 793 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	-0.80
CADD	Benign	2.1
DANN	Benign	0.71

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: rs2286407; hg19: chr17-27576299;