Genetic Variant NM_139161.5:c.26T>C (chr19-6464727-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_139161.5(CRB3):c.26T>C(p.Leu9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,248,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CRB3
NM_139161.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.950

Publications

0 publications found

Variant links:

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]

CRB3 links:

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]

SLC25A23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021707535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139161.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRB3	NM_139161.5	MANE Select	c.26T>C	p.Leu9Pro	missense	Exon 2 of 4	NP_631900.1	Q9BUF7-1
CRB3	NM_174881.4		c.26T>C	p.Leu9Pro	missense	Exon 2 of 5	NP_777377.1	Q9BUF7-2
CRB3	NM_174882.3		c.26T>C	p.Leu9Pro	missense	Exon 2 of 4	NP_777378.1	Q9BUF7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRB3	ENST00000600229.6	TSL:2 MANE Select	c.26T>C	p.Leu9Pro	missense	Exon 2 of 4	ENSP00000472010.1	Q9BUF7-1
CRB3	ENST00000356762.7	TSL:1	c.26T>C	p.Leu9Pro	missense	Exon 2 of 5	ENSP00000349204.2	Q9BUF7-2
CRB3	ENST00000308243.7	TSL:2	c.26T>C	p.Leu9Pro	missense	Exon 1 of 3	ENSP00000310123.6	Q9BUF7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000972

AC:

AN:

20568

AF XY:

0.000166

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1096722

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

519830

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23782

American (AMR)

AF:

0.00

AC:

AN:

9736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14544

East Asian (EAS)

AF:

0.00

AC:

AN:

27842

South Asian (SAS)

AF:

0.000717

AC:

AN:

20908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

928006

Other (OTH)

AF:

0.00

AC:

AN:

44326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000291

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.35

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.4

PhyloP100

0.95

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.63

MutPred

0.57

Gain of loop (P = 0.0045)

MVP

0.67

MPC

1.4

ClinPred

0.50

GERP RS

4.0

PromoterAI

0.041

Neutral

(source)

Varity_R

0.57

gMVP

0.58

Mutation Taster

=70/30

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over