rs142203406

Variant names:

• chr1-26324154-G-A
• rs142203406
• NM_001039775.4:c.4735C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-26324154-G-A
• chr1-26324154-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001039775.4(CRYBG2):​c.4735C>T​(p.Gln1579*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,460,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRYBG2 NM_001039775.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.22
• Publications: 0 publications found

Genes affected

CRYBG2 (HGNC:17295): (crystallin beta-gamma domain containing 2) Predicted to enable carbohydrate binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBG2	NM_001039775.4	c.4735C>T	p.Gln1579*	stop_gained, splice_region_variant	Exon 18 of 20	ENST00000308182.10	NP_001034864.2
CRYBG2	XM_011541673.3	c.4906C>T	p.Gln1636*	stop_gained, splice_region_variant	Exon 18 of 20		XP_011539975.1
CRYBG2	XM_005245918.3	c.4735C>T	p.Gln1579*	stop_gained, splice_region_variant	Exon 18 of 20		XP_005245975.1
CRYBG2	XM_011541672.2	c.4699C>T	p.Gln1567*	stop_gained, splice_region_variant	Exon 17 of 19		XP_011539974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBG2	ENST00000308182.10	c.4735C>T	p.Gln1579*	stop_gained, splice_region_variant	Exon 18 of 20	5	NM_001039775.4	ENSP00000310435.6
CRYBG2	ENST00000475866.3	c.5707C>T	p.Gln1903*	stop_gained, splice_region_variant	Exon 20 of 22	4		ENSP00000428746.2
CRYBG2	ENST00000374208.1	n.213C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	5
CRYBG2	ENST00000374211.5	n.349C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250444 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460976 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726770

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111710

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		6.2
Vest4		0.22
GERP RS		5.5
Mutation Taster		=8/192	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: 42

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

Other links and lift over

dbSNP: rs142203406; hg19: chr1-26650645;