chr1-89583197-C-T

Position:

• chr1-89583197-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001369817.2(LRRC8B):​c.547C>T​(p.Leu183Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC8B NM_001369817.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.123

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRRC8B
• BP4: Computational evidence support a benign effect (MetaRNN=0.038669437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC8B	NM_001369817.2	c.547C>T	p.Leu183Phe	missense_variant	5/6	ENST00000330947.7
LRRC8B	NM_001134476.2	c.547C>T	p.Leu183Phe	missense_variant	7/8
LRRC8B	NM_001369819.2	c.547C>T	p.Leu183Phe	missense_variant	6/7
LRRC8B	NM_015350.4	c.547C>T	p.Leu183Phe	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC8B	ENST00000330947.7	c.547C>T	p.Leu183Phe	missense_variant	5/6	5	NM_001369817.2	P1
LRRC8C-DT	ENST00000655657.3	n.928G>A		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Jan 23, 2024

The c.547C>T (p.L183F) alteration is located in exon 5 (coding exon 1) of the LRRC8B gene. This alteration results from a C to T substitution at nucleotide position 547, causing the leucine (L) at amino acid position 183 to be replaced by a phenylalanine (F). 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	0.061
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.023	T;T;T;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.039	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
Polyphen		0.0	B;B;B;B;.
Vest4		0.065, 0.070, 0.056
MutPred		0.18		Gain of methylation at K182 (P = 0.0302);Gain of methylation at K182 (P = 0.0302);Gain of methylation at K182 (P = 0.0302);Gain of methylation at K182 (P = 0.0302);Gain of methylation at K182 (P = 0.0302);
MVP		0.043
MPC		0.56
ClinPred		0.029	T
GERP RS		0.71
Varity_R		0.028
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-90048756;