Variant 1-89713970-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032270.5(LRRC8C):c.1400A>T(p.Asp467Val) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,613,574 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 6 hom. )

Consequence

LRRC8C
NM_032270.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.35

Variant links:

Genes affected

LRRC8C (HGNC:25075): (leucine rich repeat containing 8 VRAC subunit C) Enables volume-sensitive anion channel activity. Involved in cyclic-GMP-AMP transmembrane import across plasma membrane. Located in cytoplasm and plasma membrane. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC8C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03600335).

BS2

High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC8C	NM_032270.5 linkuse as main transcript	c.1400A>T	p.Asp467Val	missense_variant	3/3	ENST00000370454.9	NP_115646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC8C	ENST00000370454.9 linkuse as main transcript	c.1400A>T	p.Asp467Val	missense_variant	3/3	1	NM_032270.5	ENSP00000359483	P1
LRRC8C	ENST00000479252.1 linkuse as main transcript	n.393+27359A>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000634

AC:

159

AN:

250758

Hom.:

AF XY:

0.000656

AC XY:

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000712

Gnomad NFE exome

AF:

0.000985

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00124

AC:

1817

AN:

1461260

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

862

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000568

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152314

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000968

Hom.:

Bravo

AF:

0.000827

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000667

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.1400A>T (p.D467V) alteration is located in exon 3 (coding exon 2) of the LRRC8C gene. This alteration results from a A to T substitution at nucleotide position 1400, causing the aspartic acid (D) at amino acid position 467 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.0028

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.043

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0066

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.26

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.090

REVEL

Benign

0.28

Sift

Benign

0.85

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.49

MVP

0.59

MPC

0.68

ClinPred

0.024

GERP RS

4.6

Varity_R

0.19

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over