4-101829918-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017935.5(BANK1):c.181C>T(p.Arg61Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: BANK1 NM_017935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.68

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04418215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BANK1	NM_017935.5	c.181C>T	p.Arg61Cys	missense_variant	2/17	ENST00000322953.9
BANK1	NM_001083907.3	c.91C>T	p.Arg31Cys	missense_variant	2/17
BANK1	NM_001127507.3	c.71-25117C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BANK1	ENST00000322953.9	c.181C>T	p.Arg61Cys	missense_variant	2/17	1	NM_017935.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251254 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The c.181C>T (p.R61C) alteration is located in exon 2 (coding exon 2) of the BANK1 gene. This alteration results from a C to T substitution at nucleotide position 181, causing the arginine (R) at amino acid position 61 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.93
Dann	Benign	0.95
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.033	B;B;.
Vest4		0.10
MutPred		0.45		.;Gain of catalytic residue at E63 (P = 0.1032);.;
MVP		0.27
MPC		0.024
ClinPred		0.026	T
GERP RS		-2.0
Varity_R		0.079
gMVP		0.26

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: rs769134760; hg19: chr4-102751075; COSMIC: COSV59844918;