chr1-26322226-C-T

Variant names:

• chr1-26322226-C-T
• rs756304822
• NM_001039775.4:c.4835G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039775.4(CRYBG2):​c.4835G>A​(p.Ser1612Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CRYBG2 NM_001039775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20589298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBG2	NM_001039775.4	c.4835G>A	p.Ser1612Asn	missense_variant	Exon 19 of 20	ENST00000308182.10	NP_001034864.2
CRYBG2	XM_011541673.3	c.5006G>A	p.Ser1669Asn	missense_variant	Exon 19 of 20		XP_011539975.1
CRYBG2	XM_005245918.3	c.4835G>A	p.Ser1612Asn	missense_variant	Exon 19 of 20		XP_005245975.1
CRYBG2	XM_011541672.2	c.4799G>A	p.Ser1600Asn	missense_variant	Exon 18 of 19		XP_011539974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBG2	ENST00000308182.10	c.4835G>A	p.Ser1612Asn	missense_variant	Exon 19 of 20	5	NM_001039775.4	ENSP00000310435.6
CRYBG2	ENST00000475866.3	c.5807G>A	p.Ser1936Asn	missense_variant	Exon 21 of 22	4		ENSP00000428746.2
CRYBG2	ENST00000374208.1	n.313G>A		non_coding_transcript_exon_variant	Exon 3 of 4	5
CRYBG2	ENST00000374211.5	n.449G>A		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251432 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135896

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4835G>A (p.S1612N) alteration is located in exon 19 (coding exon 18) of the AIM1L gene. This alteration results from a G to A substitution at nucleotide position 4835, causing the serine (S) at amino acid position 1612 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.52	T
REVEL	Benign	0.083
Sift4G	Benign	0.073	.;T
Vest4		0.26
MVP		0.38
ClinPred		0.70	D
GERP RS		3.1
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs756304822; hg19: chr1-26648717; COSMIC: COSV100366880; COSMIC: COSV100366880;