1-26336871-C-T

Variant names:

• chr1-26336871-C-T
• rs10751735
• NM_001039775.4:c.3881G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001039775.4(CRYBG2):​c.3881G>A​(p.Ser1294Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 1,604,620 control chromosomes in the GnomAD database, including 211,231 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1294R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (22544 hom., cov: 32)
  • Exomes 𝑓: 0.50 (188687 hom.)
• Consequence: CRYBG2 NM_001039775.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6746806E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBG2	NM_001039775.4	c.3881G>A	p.Ser1294Asn	missense_variant	Exon 11 of 20	ENST00000308182.10	NP_001034864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBG2	ENST00000308182.10	c.3881G>A	p.Ser1294Asn	missense_variant	Exon 11 of 20	5	NM_001039775.4	ENSP00000310435.6

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81191 AN: 151882 Hom.: 22505 Cov.: 32

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.538

GnomAD3 exomes AF: 0.477 AC: 111255 AN: 233002 Hom.: 28053 AF XY: 0.483 AC XY: 60900 AN XY: 126134

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.454

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.530

Gnomad OTH exome AF: 0.501

GnomAD4 exome AF: 0.505 AC: 732889 AN: 1452620 Hom.: 188687 Cov.: 95 AF XY: 0.504 AC XY: 363556 AN XY: 721834

Gnomad4 AFR exome AF: 0.646

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.601

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.456

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.518

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.535 AC: 81270 AN: 152000 Hom.: 22544 Cov.: 32 AF XY: 0.531 AC XY: 39421 AN XY: 74266

Gnomad4 AFR AF: 0.639

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.603

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.534

Alfa AF: 0.522 Hom.: 40343

Bravo AF: 0.534

TwinsUK AF: 0.505 AC: 1871

ALSPAC AF: 0.524 AC: 2020

ESP6500AA AF: 0.631 AC: 2781

ESP6500EA AF: 0.525 AC: 4510

ExAC AF: 0.477 AC: 57798

Asia WGS AF: 0.326 AC: 1134 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.8
DANN	Benign	0.95
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.27	T;T;T
MetaRNN	Benign	0.000017	T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.30	T
REVEL	Benign	0.12
Sift4G	Benign	0.63	.;T;.
Vest4		0.12
MPC		0.92
ClinPred		0.0071	T
GERP RS		-3.5
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10751735; hg19: chr1-26663362; COSMIC: COSV57484854; COSMIC: COSV57484854;