11-61956976-T-C

Position:

• chr11-61956976-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_004183.4(BEST1):​c.614T>C​(p.Ile205Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.09

Genes affected

BEST1 (HGNC:12703): (bestrophin 1) This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]

BEST1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Extracellular (size 28) in uniprot entity BEST1_HUMAN there are 50 pathogenic changes around while only 1 benign (98%) in NM_004183.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 11-61956976-T-C is Pathogenic according to our data. Variant chr11-61956976-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2747.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-61956976-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BEST1	NM_004183.4	c.614T>C	p.Ile205Thr	missense_variant	5/11	ENST00000378043.9	NP_004174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9	c.614T>C	p.Ile205Thr	missense_variant	5/11	1	NM_004183.4	ENSP00000367282.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BEST1 function (PMID: 19853238). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2747). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa and autosomal dominant macular dystrophy (PMID: 19853238, 26716959). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 205 of the BEST1 protein (p.Ile205Thr). -

Retinitis pigmentosa 50 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.;D
Eigen	Benign	0.059
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D;D;N
REVEL	Pathogenic	0.75
Sift	Benign	0.063	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.68	P;P;B
Vest4		0.59
MutPred		0.79		Loss of stability (P = 0.0285);.;.;
MVP		0.98
MPC		0.44
ClinPred		0.65	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267606680; hg19: chr11-61724448;