Genetic Variant NM_001134479.2:c.697A>G (chr1-89933765-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001134479.2(LRRC8D):c.697A>G(p.Thr233Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

LRRC8D
NM_001134479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.43

Publications

0 publications found

Variant links:

Genes affected

LRRC8D (HGNC:16992): (leucine rich repeat containing 8 VRAC subunit D) Enables volume-sensitive anion channel activity. Involved in cellular response to osmotic stress; organic acid transport; and protein hexamerization. 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]

LRRC8D links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.093180925).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134479.2. 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
	LRRC8D	NM_001134479.2	MANE Select	c.697A>G	p.Thr233Ala	missense	Exon 3 of 3	NP_001127951.1	Q7L1W4
	LRRC8D	NM_018103.5		c.697A>G	p.Thr233Ala	missense	Exon 3 of 3	NP_060573.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC8D	ENST00000337338.9	TSL:2 MANE Select	c.697A>G	p.Thr233Ala	missense	Exon 3 of 3	ENSP00000338887.5	Q7L1W4
LRRC8D	ENST00000394593.7	TSL:1	c.697A>G	p.Thr233Ala	missense	Exon 3 of 3	ENSP00000378093.3	Q7L1W4
LRRC8D	ENST00000906496.1		c.697A>G	p.Thr233Ala	missense	Exon 3 of 3	ENSP00000576555.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250898

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.013

Eigen

Benign

-0.11

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

M_CAP

Benign

0.0088

MetaRNN

Benign

0.093

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

2.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.24

REVEL

Benign

0.035

Sift

Benign

0.34

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.078

MutPred

0.20

Loss of helix (P = 0.0017)

MVP

0.16

MPC

0.57

ClinPred

0.10

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.35

Mutation Taster

=60/40

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over