rs56117601

Variant names:

• chr22-26625625-A-G
• rs56117601
• NM_001886.3:c.300+3A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001886.3(CRYBA4):​c.300+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,613,254 control chromosomes in the GnomAD database, including 2,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (375 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2045 hom.)
• Consequence: CRYBA4 NM_001886.3 splice_region, intron
• Scores: Splicing: ADA: 0.01743
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.10
• Publications: 6 publications found

Genes affected

CRYBA4 (HGNC:2396): (crystallin beta A4) 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, is part of a gene cluster with beta-B1, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

CRYBA4 Gene-Disease associations (from GenCC):

• cataract 23

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cataract - microcornea syndrome

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 22-26625625-A-G is Benign according to our data. Variant chr22-26625625-A-G is described in ClinVar as Benign. ClinVar VariationId is 258488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001886.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	NM_001886.3	MANE Select	c.300+3A>G		splice_region intron	N/A	NP_001877.1	A0A097PIJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	ENST00000354760.4	TSL:1 MANE Select	c.300+3A>G		splice_region intron	N/A	ENSP00000346805.3	P53673
	CRYBA4	ENST00000466315.1	TSL:5	n.197+3A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9766 AN: 151978 Hom.: 375 Cov.: 32

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0555

Gnomad ASJ AF: 0.0853

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.0727

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.0605 AC: 15167 AN: 250636 AF XY: 0.0606

Gnomad AFR exome AF: 0.0795

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.0772

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0627

GnomAD4 exome AF: 0.0472 AC: 69012 AN: 1461158 Hom.: 2045 Cov.: 34 AF XY: 0.0478 AC XY: 34771 AN XY: 726868

African (AFR) AF: 0.0845 AC: 2827 AN: 33460

American (AMR) AF: 0.0362 AC: 1619 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0792 AC: 2070 AN: 26122

East Asian (EAS) AF: 0.0800 AC: 3175 AN: 39694

South Asian (SAS) AF: 0.0635 AC: 5478 AN: 86230

European-Finnish (FIN) AF: 0.115 AC: 6114 AN: 53052

Middle Eastern (MID) AF: 0.106 AC: 610 AN: 5758

European-Non Finnish (NFE) AF: 0.0391 AC: 43466 AN: 1111784

Other (OTH) AF: 0.0605 AC: 3653 AN: 60370

GnomAD4 genome AF: 0.0643 AC: 9779 AN: 152096 Hom.: 375 Cov.: 32 AF XY: 0.0675 AC XY: 5019 AN XY: 74352

African (AFR) AF: 0.0810 AC: 3363 AN: 41506

American (AMR) AF: 0.0554 AC: 847 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0853 AC: 296 AN: 3472

East Asian (EAS) AF: 0.0952 AC: 491 AN: 5160

South Asian (SAS) AF: 0.0729 AC: 351 AN: 4812

European-Finnish (FIN) AF: 0.118 AC: 1244 AN: 10568

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0439 AC: 2986 AN: 67970

Other (OTH) AF: 0.0752 AC: 159 AN: 2114

Alfa AF: 0.0511 Hom.: 98

Bravo AF: 0.0576

Asia WGS AF: 0.134 AC: 466 AN: 3478

EpiCase AF: 0.0473

EpiControl AF: 0.0476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cataract 23 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		2.1
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56117601; hg19: chr22-27021589;