1-89583512-G-A

Position:

• chr1-89583512-G-A

Variant summary

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

The NM_001369817.2(LRRC8B):​c.862G>A​(p.Asp288Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,613,332 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (125 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (107 hom.)
• Consequence: LRRC8B NM_001369817.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.24

Genes affected

LRRC8B (HGNC:30692): (leucine rich repeat containing 8 VRAC subunit B) Contributes to volume-sensitive anion channel activity. Involved in anion transmembrane transport. Located in cytoplasm and plasma membrane. Is integral component of plasma membrane. Part of ion channel complex. [provided by Alliance of Genome Resources, Apr 2022]

LRRC8C-DT (HGNC:53731): (LRRC8C divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035030544).
• BP6: Variant 1-89583512-G-A is Benign according to our data. Variant chr1-89583512-G-A is described in ClinVar as [Benign]. Clinvar id is 782380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC8B	NM_001369817.2	c.862G>A	p.Asp288Asn	missense_variant	5/6	ENST00000330947.7
LRRC8B	NM_001134476.2	c.862G>A	p.Asp288Asn	missense_variant	7/8
LRRC8B	NM_001369819.2	c.862G>A	p.Asp288Asn	missense_variant	6/7
LRRC8B	NM_015350.4	c.862G>A	p.Asp288Asn	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC8B	ENST00000330947.7	c.862G>A	p.Asp288Asn	missense_variant	5/6	5	NM_001369817.2	P1
LRRC8C-DT	ENST00000655657.3	n.701-88C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3268 AN: 152138 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0752

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00537 AC: 1345 AN: 250366 Hom.: 46 AF XY: 0.00383 AC XY: 518 AN XY: 135360

Gnomad AFR exome AF: 0.0744

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00214 AC: 3120 AN: 1461076 Hom.: 107 Cov.: 34 AF XY: 0.00180 AC XY: 1312 AN XY: 726908

Gnomad4 AFR exome AF: 0.0758

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000953

Gnomad4 OTH exome AF: 0.00480

GnomAD4 genome AF: 0.0215 AC: 3281 AN: 152256 Hom.: 125 Cov.: 32 AF XY: 0.0203 AC XY: 1509 AN XY: 74444

Gnomad4 AFR AF: 0.0753

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00464 Hom.: 35

Bravo AF: 0.0240

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0717 AC: 316

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00661 AC: 802

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T;T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;.;.;T
MetaRNN	Benign	0.0035	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M
MutationTaster	Benign	0.87	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.88	.;.;N;N
REVEL	Benign	0.15
Sift	Benign	0.49	.;.;T;T
Sift4G	Benign	0.50	.;.;T;T
Polyphen		0.95	P;P;P;P
Vest4		0.48, 0.47
MVP		0.17
MPC		1.4
ClinPred		0.029	T
GERP RS		5.3
Varity_R		0.21
gMVP		0.70

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: rs17131746; hg19: chr1-90049071;