rs757194662

Variant names:

• chr19-6466505-C-G
• rs757194662
• NM_139161.5:c.196C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-6466505-C-G
• chr19-6466505-C-T

Variant summary

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

The NM_139161.5(CRB3):​c.196C>G​(p.Leu66Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L66F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRB3 NM_139161.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.562

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]

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=0.03213942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB3	NM_139161.5	c.196C>G	p.Leu66Val	missense_variant	Exon 4 of 4	ENST00000600229.6	NP_631900.1
CRB3	NM_174881.4	c.196C>G	p.Leu66Val	missense_variant	Exon 4 of 5		NP_777377.1
CRB3	NM_174882.3	c.196C>G	p.Leu66Val	missense_variant	Exon 4 of 4		NP_777378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB3	ENST00000600229.6	c.196C>G	p.Leu66Val	missense_variant	Exon 4 of 4	2	NM_139161.5	ENSP00000472010.1
CRB3	ENST00000356762.7	c.196C>G	p.Leu66Val	missense_variant	Exon 4 of 5	1		ENSP00000349204.2
CRB3	ENST00000308243.7	c.196C>G	p.Leu66Val	missense_variant	Exon 3 of 3	2		ENSP00000310123.6
CRB3	ENST00000598494.5	c.196C>G	p.Leu66Val	missense_variant	Exon 4 of 4	2		ENSP00000469707.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250470 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135454

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: 1461568 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.9
DANN	Benign	0.88
DEOGEN2	Benign	0.031	T;T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.45	.;.;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.24	.;.;N;N
REVEL	Benign	0.066
Sift	Benign	0.055	.;.;T;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.027
MutPred		0.27		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.072
MPC		0.37
ClinPred		0.042	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.035
gMVP		0.45

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: rs757194662; hg19: chr19-6466516;