rs2736597

Variant names:

• chr11-61950564-G-A
• rs2736597
• NM_004183.4:c.-37+137G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61950564-G-A
• chr11-61950564-G-C
• chr11-61950564-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004183.4(BEST1):​c.-37+137G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,202 control chromosomes in the GnomAD database, including 21,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (21269 hom., cov: 32)
  • Exomes 𝑓: 0.45 (17 hom.)
• Consequence: BEST1 NM_004183.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.99
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant vitreoretinochoroidopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• inherited retinal dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• vitelliform macular dystrophy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal recessive bestrophinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 50

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• adult-onset foveomacular vitelliform dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• MRCS syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-61950564-G-A is Benign according to our data. Variant chr11-61950564-G-A is described in ClinVar as [Benign]. Clinvar id is 1273545.Status of the report is criteria_provided_single_submitter, 1 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 rank	MANE	Protein	UniProt
BEST1	NM_004183.4	c.-37+137G>A		intron_variant	Intron 1 of 10	ENST00000378043.9	NP_004174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9	c.-37+137G>A		intron_variant	Intron 1 of 10	1	NM_004183.4	ENSP00000367282.4

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74546 AN: 151934 Hom.: 21233 Cov.: 32

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.453 AC: 68 AN: 150 Hom.: 17 AF XY: 0.448 AC XY: 43 AN XY: 96

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.455 AC: 61 AN: 134

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 4 AN: 8

Other (OTH) AF: 0.375 AC: 3 AN: 8

GnomAD4 genome AF: 0.491 AC: 74635 AN: 152052 Hom.: 21269 Cov.: 32 AF XY: 0.503 AC XY: 37379 AN XY: 74326

African (AFR) AF: 0.728 AC: 30198 AN: 41482

American (AMR) AF: 0.492 AC: 7509 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 969 AN: 3470

East Asian (EAS) AF: 0.911 AC: 4710 AN: 5172

South Asian (SAS) AF: 0.714 AC: 3446 AN: 4824

European-Finnish (FIN) AF: 0.461 AC: 4866 AN: 10560

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21787 AN: 67950

Other (OTH) AF: 0.417 AC: 882 AN: 2116

Alfa AF: 0.423 Hom.: 2462

Bravo AF: 0.501

Asia WGS AF: 0.768 AC: 2667 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.62
PhyloP100		2.0
PromoterAI		-0.023	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2736597; hg19: chr11-61718036;