1-26324186-A-G

Variant names:

• chr1-26324186-A-G
• rs1464464760
• NM_001039775.4:c.4703T>C

Variant summary

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

The NM_001039775.4(CRYBG2):​c.4703T>C​(p.Ile1568Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRYBG2 NM_001039775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.31

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBG2	NM_001039775.4	c.4703T>C	p.Ile1568Thr	missense_variant	Exon 18 of 20	ENST00000308182.10	NP_001034864.2
CRYBG2	XM_011541673.3	c.4874T>C	p.Ile1625Thr	missense_variant	Exon 18 of 20		XP_011539975.1
CRYBG2	XM_005245918.3	c.4703T>C	p.Ile1568Thr	missense_variant	Exon 18 of 20		XP_005245975.1
CRYBG2	XM_011541672.2	c.4667T>C	p.Ile1556Thr	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.4703T>C	p.Ile1568Thr	missense_variant	Exon 18 of 20	5	NM_001039775.4	ENSP00000310435.6
CRYBG2	ENST00000475866.3	c.5675T>C	p.Ile1892Thr	missense_variant	Exon 20 of 22	4		ENSP00000428746.2
CRYBG2	ENST00000374208.1	n.181T>C		non_coding_transcript_exon_variant	Exon 2 of 4	5
CRYBG2	ENST00000374211.5	n.317T>C		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251032 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135726

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: 0.0000327

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: 1461524 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727092

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4703T>C (p.I1568T) alteration is located in exon 18 (coding exon 17) of the AIM1L gene. This alteration results from a T to C substitution at nucleotide position 4703, causing the isoleucine (I) at amino acid position 1568 to be replaced by a threonine (T). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.80	T
PrimateAI	Uncertain	0.52	T
REVEL	Uncertain	0.45
Sift4G	Uncertain	0.0030	.;D
Vest4		0.76
MVP		0.67
ClinPred		0.97	D
GERP RS		5.5
gMVP		0.55

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: rs1464464760; hg19: chr1-26650677;