rs12032393

Variant names:

• chr1-89713973-A-G
• rs12032393
• NM_032270.5:c.1403A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032270.5(LRRC8C):​c.1403A>G​(p.Asn468Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,052 control chromosomes in the GnomAD database, including 18,839 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1515 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17324 hom.)
• Consequence: LRRC8C NM_032270.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000271949 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018877089).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8C	NM_032270.5	c.1403A>G	p.Asn468Ser	missense_variant	Exon 3 of 3	ENST00000370454.9	NP_115646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC8C	ENST00000370454.9	c.1403A>G	p.Asn468Ser	missense_variant	Exon 3 of 3	1	NM_032270.5	ENSP00000359483.4
ENSG00000271949	ENST00000370453.5	n.138+27362A>G		intron_variant	Intron 2 of 3	5		ENSP00000359482.5
LRRC8C	ENST00000479252.1	n.393+27362A>G		intron_variant	Intron 2 of 3	1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19283 AN: 152002 Hom.: 1517 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.164 AC: 41165 AN: 250646 AF XY: 0.163

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.274

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.149 AC: 217276 AN: 1460932 Hom.: 17324 Cov.: 36 AF XY: 0.149 AC XY: 108262 AN XY: 726846

African (AFR) AF: 0.0367 AC: 1227 AN: 33476

American (AMR) AF: 0.238 AC: 10638 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2934 AN: 26136

East Asian (EAS) AF: 0.276 AC: 10962 AN: 39698

South Asian (SAS) AF: 0.176 AC: 15216 AN: 86256

European-Finnish (FIN) AF: 0.166 AC: 8751 AN: 52674

Middle Eastern (MID) AF: 0.136 AC: 787 AN: 5768

European-Non Finnish (NFE) AF: 0.142 AC: 157863 AN: 1111818

Other (OTH) AF: 0.147 AC: 8898 AN: 60382

GnomAD4 genome AF: 0.127 AC: 19283 AN: 152120 Hom.: 1515 Cov.: 32 AF XY: 0.129 AC XY: 9612 AN XY: 74366

African (AFR) AF: 0.0430 AC: 1786 AN: 41520

American (AMR) AF: 0.204 AC: 3111 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 382 AN: 3468

East Asian (EAS) AF: 0.260 AC: 1341 AN: 5166

South Asian (SAS) AF: 0.178 AC: 856 AN: 4816

European-Finnish (FIN) AF: 0.165 AC: 1742 AN: 10566

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9605 AN: 67994

Other (OTH) AF: 0.129 AC: 273 AN: 2112

Alfa AF: 0.140 Hom.: 5425

Bravo AF: 0.128

TwinsUK AF: 0.142 AC: 525

ALSPAC AF: 0.140 AC: 538

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.144 AC: 1235

ExAC AF: 0.157 AC: 19063

Asia WGS AF: 0.199 AC: 694 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.20	T
Sift4G	Benign	0.23	T
Polyphen		0.10	B
Vest4		0.018
MPC		0.37
ClinPred		0.018	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.35
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12032393; hg19: chr1-90179532; COSMIC: COSV65001963;