17-29252605-C-T

Variant names:

• chr17-29252605-C-T
• rs8080081
• NM_005208.5:c.357+400C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005208.5(CRYBA1):​c.357+400C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 116,556 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0054 (0 hom., cov: 29)
• Consequence: CRYBA1 NM_005208.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• Publications: 8 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005208.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA1	NM_005208.5	MANE Select	c.357+400C>T		intron	N/A	NP_005199.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA1	ENST00000225387.8	TSL:1 MANE Select	c.357+400C>T		intron	N/A	ENSP00000225387.3
	CRYBA1	ENST00000484605.1	TSL:5	n.204-1035C>T		intron	N/A	ENSP00000464368.1

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 624 AN: 116440 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00621

Gnomad AMI AF: 0.00573

Gnomad AMR AF: 0.00619

Gnomad ASJ AF: 0.00511

Gnomad EAS AF: 0.00480

Gnomad SAS AF: 0.00320

Gnomad FIN AF: 0.00219

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00702

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00536 AC: 625 AN: 116556 Hom.: 0 Cov.: 29 AF XY: 0.00504 AC XY: 290 AN XY: 57558

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00619 AC: 207 AN: 33456

American (AMR) AF: 0.00619 AC: 69 AN: 11152

Ashkenazi Jewish (ASJ) AF: 0.00511 AC: 13 AN: 2544

East Asian (EAS) AF: 0.00481 AC: 21 AN: 4364

South Asian (SAS) AF: 0.00321 AC: 13 AN: 4056

European-Finnish (FIN) AF: 0.00219 AC: 19 AN: 8666

Middle Eastern (MID) AF: 0.0156 AC: 3 AN: 192

European-Non Finnish (NFE) AF: 0.00532 AC: 265 AN: 49842

Other (OTH) AF: 0.00694 AC: 11 AN: 1586

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 207

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.4
DANN	Benign	0.91
PhyloP100		-0.16

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: rs8080081; hg19: chr17-27579623;