chr1-89584056-G-A

Position:

• chr1-89584056-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.1406G>A​(p.Arg469His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,614,088 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.0047 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (166 hom.)
• Consequence: LRRC8B NM_001369817.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33

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=0.0029286444).
• BP6: Variant 1-89584056-G-A is Benign according to our data. Variant chr1-89584056-G-A is described in ClinVar as [Benign]. Clinvar id is 770489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC8B	NM_001369817.2	c.1406G>A	p.Arg469His	missense_variant	5/6	ENST00000330947.7
LRRC8B	NM_001134476.2	c.1406G>A	p.Arg469His	missense_variant	7/8
LRRC8B	NM_001369819.2	c.1406G>A	p.Arg469His	missense_variant	6/7
LRRC8B	NM_015350.4	c.1406G>A	p.Arg469His	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC8B	ENST00000330947.7	c.1406G>A	p.Arg469His	missense_variant	5/6	5	NM_001369817.2	P1
LRRC8C-DT	ENST00000655657.3	n.701-632C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 711 AN: 152158 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0259

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00938 AC: 2354 AN: 250828 Hom.: 54 AF XY: 0.00784 AC XY: 1063 AN XY: 135564

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0537

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00345 AC: 5042 AN: 1461812 Hom.: 166 Cov.: 34 AF XY: 0.00322 AC XY: 2342 AN XY: 727206

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0346

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0764

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152276 Hom.: 18 Cov.: 32 AF XY: 0.00537 AC XY: 400 AN XY: 74442

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.0259

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0509

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00306 Hom.: 13

Bravo AF: 0.00719

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00825 AC: 1001

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Dec 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.7
DANN	Benign	0.71
DEOGEN2	Benign	0.037	T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.68	.;.;.;T
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N;N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	2.7	.;.;N;N
REVEL	Benign	0.019
Sift	Benign	1.0	.;.;T;T
Sift4G	Benign	0.65	.;.;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.074, 0.060
MVP		0.043
MPC		0.64
ClinPred		0.00058	T
GERP RS		-0.63
Varity_R		0.0087
gMVP		0.12

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: rs3795832; hg19: chr1-90049615;