NM_005208.5:c.96+75T>G

Variant names:

• chr17-29249281-T-G
• rs2286407
• NM_005208.5:c.96+75T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

CRYBA1 Gene-Disease associations (from GenCC):

• cataract 10 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CRYBA1	NM_005208.5	c.96+75T>G		intron_variant	Intron 2 of 5	ENST00000225387.8	NP_005199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA1	ENST00000225387.8	c.96+75T>G		intron_variant	Intron 2 of 5	1	NM_005208.5	ENSP00000225387.3
CRYBA1	ENST00000484605.1	n.84+75T>G		intron_variant	Intron 2 of 4	5		ENSP00000464368.1

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

African (AFR) AF: 0.167 AC: 3754 AN: 22490

American (AMR) AF: 0.126 AC: 5304 AN: 42040

Ashkenazi Jewish (ASJ) AF: 0.0958 AC: 2104 AN: 21962

East Asian (EAS) AF: 0.317 AC: 11774 AN: 37088

South Asian (SAS) AF: 0.167 AC: 12529 AN: 74860

European-Finnish (FIN) AF: 0.111 AC: 5628 AN: 50664

Middle Eastern (MID) AF: 0.0867 AC: 403 AN: 4646

European-Non Finnish (NFE) AF: 0.0956 AC: 57410 AN: 600522

Other (OTH) AF: 0.115 AC: 4772 AN: 41604

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

African (AFR) AF: 0.172 AC: 7132 AN: 41462

American (AMR) AF: 0.106 AC: 1619 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3470

East Asian (EAS) AF: 0.298 AC: 1534 AN: 5148

South Asian (SAS) AF: 0.172 AC: 830 AN: 4814

European-Finnish (FIN) AF: 0.117 AC: 1232 AN: 10550

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0977 AC: 6639 AN: 67952

Other (OTH) AF: 0.113 AC: 239 AN: 2108

Alfa AF: 0.108 Hom.: 3797

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.1
DANN	Benign	0.71
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2286407; hg19: chr17-27576299; COSMIC: COSV107307875;