19-6464723-C-A

Variant names:

• chr19-6464723-C-A
• rs769620076
• NM_139161.5:c.22C>A

Variant summary

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

The NM_139161.5(CRB3):​c.22C>A​(p.Leu8Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 9.1e-7 (0 hom.)
• Consequence: CRB3 NM_139161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0640

Genes affected

CRB3 (HGNC:20237): (crumbs cell polarity complex component 3) This gene encodes a member of the Crumbs family of proteins. This gene is widely expressed in epithelial tissues where the encoded protein isoforms play various roles such as the control of cytokinesis and ciliogenesis or the formation of tight junctions. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

SLC25A23 (HGNC:19375): (solute carrier family 25 member 23) Predicted to enable ATP transmembrane transporter activity. Involved in calcium import into the mitochondrion; positive regulation of mitochondrial calcium ion concentration; and regulation of cellular hyperosmotic salinity response. Located in mitochondrion. [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=0.2093117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB3	NM_139161.5	c.22C>A	p.Leu8Met	missense_variant	Exon 2 of 4	ENST00000600229.6	NP_631900.1
CRB3	NM_174881.4	c.22C>A	p.Leu8Met	missense_variant	Exon 2 of 5		NP_777377.1
CRB3	NM_174882.3	c.22C>A	p.Leu8Met	missense_variant	Exon 2 of 4		NP_777378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB3	ENST00000600229.6	c.22C>A	p.Leu8Met	missense_variant	Exon 2 of 4	2	NM_139161.5	ENSP00000472010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094378 Hom.: 0 Cov.: 30 AF XY: 0.00000193 AC XY: 1 AN XY: 518456

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: 0.00000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22C>A (p.L8M) alteration is located in exon 2 (coding exon 1) of the CRB3 gene. This alteration results from a C to A substitution at nucleotide position 22, causing the leucine (L) at amino acid position 8 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;T;.;T
Eigen	Benign	0.19
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.32	.;.;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M;M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.59	.;.;N;N
REVEL	Benign	0.068
Sift	Benign	0.19	.;.;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.97	D;D;D;D
Vest4		0.33
MutPred		0.26		Gain of disorder (P = 0.1375);Gain of disorder (P = 0.1375);Gain of disorder (P = 0.1375);Gain of disorder (P = 0.1375);
MVP		0.11
MPC		0.99
ClinPred		0.81	D
GERP RS		2.9
Varity_R		0.079
gMVP		0.35

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: rs769620076; hg19: chr19-6464734;