1-26324211-C-T

Variant names:

• chr1-26324211-C-T
• rs765497988
• NM_001039775.4:c.4678G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039775.4(CRYBG2):​c.4678G>A​(p.Asp1560Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CRYBG2 NM_001039775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060483992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBG2	NM_001039775.4	c.4678G>A	p.Asp1560Asn	missense_variant	Exon 18 of 20	ENST00000308182.10	NP_001034864.2
CRYBG2	XM_011541673.3	c.4849G>A	p.Asp1617Asn	missense_variant	Exon 18 of 20		XP_011539975.1
CRYBG2	XM_005245918.3	c.4678G>A	p.Asp1560Asn	missense_variant	Exon 18 of 20		XP_005245975.1
CRYBG2	XM_011541672.2	c.4642G>A	p.Asp1548Asn	missense_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.4678G>A	p.Asp1560Asn	missense_variant	Exon 18 of 20	5	NM_001039775.4	ENSP00000310435.6
CRYBG2	ENST00000475866.3	c.5650G>A	p.Asp1884Asn	missense_variant	Exon 20 of 22	4		ENSP00000428746.2
CRYBG2	ENST00000374208.1	n.156G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5
CRYBG2	ENST00000374211.5	n.292G>A		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250496 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461070 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4678G>A (p.D1560N) alteration is located in exon 18 (coding exon 17) of the AIM1L gene. This alteration results from a G to A substitution at nucleotide position 4678, causing the aspartic acid (D) at amino acid position 1560 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	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.41	T
REVEL	Benign	0.045
Sift4G	Uncertain	0.021	.;D
Vest4		0.19
MVP		0.20
ClinPred		0.060	T
GERP RS		2.6
gMVP		0.26

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: rs765497988; hg19: chr1-26650702;