rs117452684

chr9-16419521-G-Achr9-16419521-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017637.6(BNC2):c.2768C>T(p.Ala923Val) variant causes a missense change. The variant allele was found at a frequency of 0.0295 in 1,614,110 control chromosomes in the GnomAD database, including 848 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A923G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (34 hom., cov: 31)
  • Exomes 𝑓: 0.031 (814 hom.)
• Consequence: BNC2 NM_017637.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 4.83

Genes affected

BNC2 (HGNC:30988): (basonuclin zinc finger protein 2) This gene encodes a conserved zinc finger protein. The encoded protein functions in skin color saturation. Mutations in this gene are associated with facial pigmented spots. This gene is also associated with susceptibility to adolescent idiopathic scoliosis. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004229605).
• BP6: Variant 9-16419521-G-A is Benign according to our data. Variant chr9-16419521-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 120238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-16419521-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0193 (2941/152246) while in subpopulation NFE AF= 0.0323 (2199/68012). AF 95% confidence interval is 0.0312. There are 34 homozygotes in gnomad4. There are 1341 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2943 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BNC2	NM_017637.6	c.2768C>T	p.Ala923Val	missense_variant	7/7	ENST00000380672.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BNC2	ENST00000380672.9	c.2768C>T	p.Ala923Val	missense_variant	7/7	2	NM_017637.6	P2

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2943 AN: 152128 Hom.: 34 Cov.: 31

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00971

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0200 AC: 5022 AN: 250660 Hom.: 79 AF XY: 0.0205 AC XY: 2776 AN XY: 135548

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00764

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0306 AC: 44667 AN: 1461864 Hom.: 814 Cov.: 35 AF XY: 0.0298 AC XY: 21702 AN XY: 727234

Gnomad4 AFR exome AF: 0.00439

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0220

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00759

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0193 AC: 2941 AN: 152246 Hom.: 34 Cov.: 31 AF XY: 0.0180 AC XY: 1341 AN XY: 74440

Gnomad4 AFR AF: 0.00544

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00971

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0296 Hom.: 123

Bravo AF: 0.0190

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0381 AC: 147

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0341 AC: 293

ExAC AF: 0.0209 AC: 2539

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0303

EpiControl AF: 0.0304

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 323/13006= 2.4% -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	BNC2: BP4, BS1, BS2 -

BNC2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypotension Other:1

not provided, no classification provided

literature only

Centre for molecular medicine, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	0.097
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.073
Sift	Benign	0.12	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.76	P;.
Vest4		0.24
MPC		0.13
ClinPred		0.014	T
GERP RS		5.5
Varity_R		0.080
gMVP		0.36

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: rs117452684; hg19: chr9-16419519;