1-26336871-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/16 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 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
• Publications: 26 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: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039775.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBG2	NM_001039775.4	MANE Select	c.3881G>A	p.Ser1294Asn	missense	Exon 11 of 20	NP_001034864.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBG2	ENST00000308182.10	TSL:5 MANE Select	c.3881G>A	p.Ser1294Asn	missense	Exon 11 of 20	ENSP00000310435.6
	CRYBG2	ENST00000522993.1	TSL:1	n.499G>A		non_coding_transcript_exon	Exon 5 of 6
	CRYBG2	ENST00000475866.3	TSL:4	c.4853G>A	p.Ser1618Asn	missense	Exon 13 of 22	ENSP00000428746.2

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

GnomAD2 exomes AF: 0.477 AC: 111255 AN: 233002 AF XY: 0.483

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 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

African (AFR) AF: 0.646 AC: 21508 AN: 33288

American (AMR) AF: 0.364 AC: 15751 AN: 43300

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15574 AN: 25926

East Asian (EAS) AF: 0.173 AC: 6789 AN: 39142

South Asian (SAS) AF: 0.456 AC: 38712 AN: 84812

European-Finnish (FIN) AF: 0.522 AC: 27394 AN: 52436

Middle Eastern (MID) AF: 0.579 AC: 3304 AN: 5708

European-Non Finnish (NFE) AF: 0.518 AC: 573764 AN: 1107994

Other (OTH) AF: 0.501 AC: 30093 AN: 60014

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

African (AFR) AF: 0.639 AC: 26480 AN: 41468

American (AMR) AF: 0.454 AC: 6942 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2094 AN: 3472

East Asian (EAS) AF: 0.178 AC: 919 AN: 5164

South Asian (SAS) AF: 0.444 AC: 2140 AN: 4824

European-Finnish (FIN) AF: 0.518 AC: 5470 AN: 10570

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35318 AN: 67906

Other (OTH) AF: 0.534 AC: 1125 AN: 2108

Alfa AF: 0.521 Hom.: 80961

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 v4.9

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
MetaRNN	Benign	0.000017	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.062
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10751735; hg19: chr1-26663362; COSMIC: COSV57484854; COSMIC: COSV57484854;