11-61950243-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363592.1(BEST1):c.-221T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,722 control chromosomes in the GnomAD database, including 21,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21296 hom., cov: 32)
  • Exomes 𝑓: 0.44 (65 hom.)
• Consequence: BEST1 NM_001363592.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-61950243-T-C is Benign according to our data. Variant chr11-61950243-T-C is described in ClinVar as [Benign]. Clinvar id is 305113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEST1	NM_001363592.1	c.-221T>C		5_prime_UTR_variant	1/10
BEST1	XM_005274210.5	c.-221T>C		5_prime_UTR_variant	1/10
BEST1	XM_005274221.5	c.-221T>C		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEST1	ENST00000534553.5	c.-396T>C		5_prime_UTR_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74628 AN: 152032 Hom.: 21260 Cov.: 32

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.417

GnomAD4 exome AF: 0.435 AC: 249 AN: 572 Hom.: 65 Cov.: 0 AF XY: 0.433 AC XY: 148 AN XY: 342

Gnomad4 EAS exome AF: 0.358

Gnomad4 FIN exome AF: 0.487

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.491 AC: 74717 AN: 152150 Hom.: 21296 Cov.: 32 AF XY: 0.503 AC XY: 37423 AN XY: 74364

Gnomad4 AFR AF: 0.728

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.911

Gnomad4 SAS AF: 0.714

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.417

Alfa AF: 0.424 Hom.: 2447

Bravo AF: 0.502

Asia WGS AF: 0.768 AC: 2667 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis Pigmentosa, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal dominant vitreoretinochoroidopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Vitelliform macular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	7.5
Dann	Benign	0.68

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: rs972353; hg19: chr11-61717715;