Genetic Variant BANK1:p.Trp40Cys (chr4-101829857-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017935.5(BANK1):c.120G>C(p.Trp40Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0167 in 1,596,420 control chromosomes in the GnomAD database, including 276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 32)

Exomes 𝑓: 0.017 ( 259 hom. )

Consequence

BANK1
NM_017935.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.88

Publications

24 publications found

Variant links:

Genes affected

BANK1 (HGNC:18233): (B cell scaffold protein with ankyrin repeats 1) The protein encoded by this gene is a B-cell-specific scaffold protein that functions in B-cell receptor-induced calcium mobilization from intracellular stores. This protein can also promote Lyn-mediated tyrosine phosphorylation of inositol 1,4,5-trisphosphate receptors. Polymorphisms in this gene are associated with susceptibility to systemic lupus erythematosus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

BANK1 Gene-Disease associations (from GenCC):

systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

BANK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007824212).

BP6

Variant 4-101829857-G-C is Benign according to our data. Variant chr4-101829857-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 619210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1695/152230) while in subpopulation NFE AF = 0.0174 (1186/68018). AF 95% confidence interval is 0.0166. There are 17 homozygotes in GnomAd4. There are 773 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017935.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BANK1	NM_017935.5	MANE Select	c.120G>C	p.Trp40Cys	missense	Exon 2 of 17	NP_060405.5
BANK1	NM_001083907.3		c.30G>C	p.Trp10Cys	missense	Exon 2 of 17	NP_001077376.3	Q8NDB2-3
BANK1	NM_001127507.3		c.71-25178G>C		intron	N/A	NP_001120979.3	Q8NDB2-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BANK1	ENST00000322953.9	TSL:1 MANE Select	c.120G>C	p.Trp40Cys	missense	Exon 2 of 17	ENSP00000320509.4	Q8NDB2-1
BANK1	ENST00000508653.5	TSL:1	c.71-25178G>C		intron	N/A	ENSP00000422314.1	Q8NDB2-4
BANK1	ENST00000504592.5	TSL:2	c.75G>C	p.Trp25Cys	missense	Exon 6 of 21	ENSP00000421443.1	Q8NDB2-2

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1695

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0117

AC:

2803

AN:

238704

AF XY:

0.0115

show subpopulations

Gnomad AFR exome

AF:

0.00269

Gnomad AMR exome

AF:

0.00917

Gnomad ASJ exome

AF:

0.0254

Gnomad EAS exome

AF:

0.0000565

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0167

GnomAD4 exome

AF:

0.0173

AC:

24914

AN:

1444190

Hom.:

259

Cov.:

AF XY:

0.0167

AC XY:

12007

AN XY:

718234

show subpopulations

African (AFR)

AF:

0.00294

AC:

AN:

32346

American (AMR)

AF:

0.00941

AC:

389

AN:

41338

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

623

AN:

25372

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39552

South Asian (SAS)

AF:

0.000940

AC:

AN:

83002

European-Finnish (FIN)

AF:

0.0146

AC:

776

AN:

53198

Middle Eastern (MID)

AF:

0.0158

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0197

AC:

21776

AN:

1104012

Other (OTH)

AF:

0.0182

AC:

1086

AN:

59674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1101

2202

3302

4403

5504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

846

1692

2538

3384

4230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0111

AC:

1695

AN:

152230

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

773

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00301

AC:

125

AN:

41548

American (AMR)

AF:

0.00798

AC:

122

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0128

AC:

135

AN:

10584

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0174

AC:

1186

AN:

68018

Other (OTH)

AF:

0.0152

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

173

259

346

432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0168

Hom.:

Bravo

AF:

0.0112

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0179

AC:

154

ExAC

AF:

0.0101

AC:

1232

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Systemic lupus erythematosus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.4

PhyloP100

6.9

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-9.5

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.61

Loss of catalytic residue at W40 (P = 7e-04)

MPC

0.20

ClinPred

0.060

GERP RS

5.2

Varity_R

0.86

gMVP

0.81

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over