rs74847916

Variant names:

• chr22-26623190-G-A
• rs74847916
• NM_001886.3:c.40-44G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-26623190-G-A
• chr22-26623190-G-C
• chr22-26623190-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001886.3(CRYBA4):​c.40-44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,527,618 control chromosomes in the GnomAD database, including 1,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (202 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1222 hom.)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.49
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 22-26623190-G-A is Benign according to our data. Variant chr22-26623190-G-A is described in ClinVar as Benign. ClinVar VariationId is 1221696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0878 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.40-44G>A		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.40-44G>A		intron	N/A	ENSP00000346805.3	P53673
	CRYBA4	ENST00000466315.1	TSL:5	n.55+555G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6830 AN: 152142 Hom.: 202 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0954

Gnomad SAS AF: 0.0680

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0475

GnomAD2 exomes AF: 0.0476 AC: 11654 AN: 244618 AF XY: 0.0481

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0445

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0341

Gnomad OTH exome AF: 0.0460

GnomAD4 exome AF: 0.0356 AC: 48947 AN: 1375360 Hom.: 1222 Cov.: 22 AF XY: 0.0365 AC XY: 25165 AN XY: 689094

African (AFR) AF: 0.0473 AC: 1507 AN: 31856

American (AMR) AF: 0.0252 AC: 1124 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 1188 AN: 25610

East Asian (EAS) AF: 0.0792 AC: 3110 AN: 39268

South Asian (SAS) AF: 0.0584 AC: 4939 AN: 84614

European-Finnish (FIN) AF: 0.102 AC: 4877 AN: 47700

Middle Eastern (MID) AF: 0.0508 AC: 285 AN: 5606

European-Non Finnish (NFE) AF: 0.0282 AC: 29336 AN: 1038456

Other (OTH) AF: 0.0448 AC: 2581 AN: 57618

GnomAD4 genome AF: 0.0449 AC: 6843 AN: 152258 Hom.: 202 Cov.: 32 AF XY: 0.0485 AC XY: 3607 AN XY: 74438

African (AFR) AF: 0.0445 AC: 1847 AN: 41546

American (AMR) AF: 0.0365 AC: 559 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3472

East Asian (EAS) AF: 0.0947 AC: 490 AN: 5174

South Asian (SAS) AF: 0.0683 AC: 330 AN: 4830

European-Finnish (FIN) AF: 0.103 AC: 1089 AN: 10592

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0326 AC: 2215 AN: 68030

Other (OTH) AF: 0.0508 AC: 107 AN: 2106

Alfa AF: 0.0282 Hom.: 26

Bravo AF: 0.0383

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.19
DANN	Benign	0.66
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74847916; hg19: chr22-27019154; COSMIC: COSV61323029;