rs3750320

Variant names:

• chr9-128908178-T-C
• rs3750320
• NM_019594.4:c.1014T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019594.4(LRRC8A):​c.1014T>C​(p.Tyr338Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,768 control chromosomes in the GnomAD database, including 33,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5162 hom., cov: 31)
  • Exomes 𝑓: 0.19 (28691 hom.)
• Consequence: LRRC8A NM_019594.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.78
• Publications: 24 publications found

Genes affected

LRRC8A (HGNC:19027): (leucine rich repeat containing 8 VRAC subunit A) This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. This family member is a putative four-pass transmembrane protein that plays a role in B cell development. Defects in this gene cause autosomal dominant non-Bruton type agammaglobulinemia, an immunodeficiency disease resulting from defects in B cell maturation. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

LRRC8A Gene-Disease associations (from GenCC):

• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• agammaglobulinemia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• agammaglobulinemia 5, autosomal dominant

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-128908178-T-C is Benign according to our data. Variant chr9-128908178-T-C is described in ClinVar as Benign. ClinVar VariationId is 403060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019594.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8A	NM_019594.4	MANE Select	c.1014T>C	p.Tyr338Tyr	synonymous	Exon 3 of 4	NP_062540.2
	LRRC8A	NM_001127244.2		c.1014T>C	p.Tyr338Tyr	synonymous	Exon 3 of 4	NP_001120716.1
	LRRC8A	NM_001127245.2		c.1014T>C	p.Tyr338Tyr	synonymous	Exon 2 of 3	NP_001120717.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8A	ENST00000372600.9	TSL:1 MANE Select	c.1014T>C	p.Tyr338Tyr	synonymous	Exon 3 of 4	ENSP00000361682.4
	LRRC8A	ENST00000372599.7	TSL:1	c.1014T>C	p.Tyr338Tyr	synonymous	Exon 2 of 3	ENSP00000361680.3
	LRRC8A	ENST00000927475.1		c.1014T>C	p.Tyr338Tyr	synonymous	Exon 3 of 5	ENSP00000597534.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36369 AN: 151884 Hom.: 5158 Cov.: 31

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.197 AC: 49560 AN: 251302 AF XY: 0.201

Gnomad AFR exome AF: 0.409

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.191 AC: 278756 AN: 1461766 Hom.: 28691 Cov.: 35 AF XY: 0.194 AC XY: 140740 AN XY: 727170

African (AFR) AF: 0.413 AC: 13836 AN: 33480

American (AMR) AF: 0.129 AC: 5750 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5346 AN: 26136

East Asian (EAS) AF: 0.212 AC: 8428 AN: 39700

South Asian (SAS) AF: 0.288 AC: 24824 AN: 86258

European-Finnish (FIN) AF: 0.124 AC: 6627 AN: 53306

Middle Eastern (MID) AF: 0.279 AC: 1607 AN: 5768

European-Non Finnish (NFE) AF: 0.180 AC: 199844 AN: 1111998

Other (OTH) AF: 0.207 AC: 12494 AN: 60396

GnomAD4 genome AF: 0.239 AC: 36395 AN: 152002 Hom.: 5162 Cov.: 31 AF XY: 0.237 AC XY: 17606 AN XY: 74278

African (AFR) AF: 0.399 AC: 16543 AN: 41418

American (AMR) AF: 0.167 AC: 2554 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 670 AN: 3470

East Asian (EAS) AF: 0.191 AC: 986 AN: 5162

South Asian (SAS) AF: 0.290 AC: 1392 AN: 4800

European-Finnish (FIN) AF: 0.126 AC: 1337 AN: 10590

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12187 AN: 67980

Other (OTH) AF: 0.248 AC: 522 AN: 2102

Alfa AF: 0.203 Hom.: 8600

Bravo AF: 0.249

Asia WGS AF: 0.201 AC: 697 AN: 3478

EpiCase AF: 0.191

EpiControl AF: 0.200

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Agammaglobulinemia 5, autosomal dominant (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.9
DANN	Benign	0.43
PhyloP100		2.8
Mutation Taster		=96/4	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: rs3750320; hg19: chr9-131670457; COSMIC: COSV52185470; COSMIC: COSV52185470;