3-97878035-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_153605.4(CRYBG3):c.6841G>A(p.Glu2281Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,597,998 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (30 hom.)
• Consequence: CRYBG3 NM_153605.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001044
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.65

Genes affected

CRYBG3 (HGNC:34427): (crystallin beta-gamma domain containing 3) Enables protein kinase A binding activity. Predicted to be involved in lens development in camera-type eye and visual perception. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072820187).
• BP6: Variant 3-97878035-G-A is Benign according to our data. Variant chr3-97878035-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2653996.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBG3	NM_153605.4	c.6841G>A	p.Glu2281Lys	missense_variant, splice_region_variant	4/22	ENST00000389622.7
CRYBG3	XM_005247117.5	c.5968G>A	p.Glu1990Lys	missense_variant, splice_region_variant	3/21
CRYBG3	XM_047447439.1	c.6841G>A	p.Glu2281Lys	missense_variant, splice_region_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBG3	ENST00000389622.7	c.6841G>A	p.Glu2281Lys	missense_variant, splice_region_variant	4/22	5	NM_153605.4	P1

Frequencies

GnomAD3 genomes AF: 0.00469 AC: 713 AN: 152146 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00672

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00397 AC: 923 AN: 232646 Hom.: 3 AF XY: 0.00423 AC XY: 537 AN XY: 126862

Gnomad AFR exome AF: 0.000272

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000450

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00923

Gnomad NFE exome AF: 0.00576

Gnomad OTH exome AF: 0.00322

GnomAD4 exome AF: 0.00575 AC: 8306 AN: 1445734 Hom.: 30 Cov.: 31 AF XY: 0.00576 AC XY: 4139 AN XY: 719080

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.00869

Gnomad4 NFE exome AF: 0.00661

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00468 AC: 713 AN: 152264 Hom.: 5 Cov.: 32 AF XY: 0.00493 AC XY: 367 AN XY: 74454

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00672

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00556 Hom.: 4

Bravo AF: 0.00405

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000835 AC: 3

ESP6500EA AF: 0.00457 AC: 37

ExAC AF: 0.00360 AC: 434

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

CRYBG3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
Sift4G	Uncertain	0.011	D
Vest4		0.21
MVP		0.31
ClinPred		0.013	T
GERP RS		3.7
Varity_R		0.043
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.016
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: rs149984020; hg19: chr3-97596879;