NM_001134479.2:c.1003T>C

Variant names:

• chr1-89934071-T-C
• NM_001134479.2:c.1003T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134479.2(LRRC8D):​c.1003T>C​(p.Phe335Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC8D NM_001134479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38512695).

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.1003T>C	p.Phe335Leu	missense	Exon 3 of 3	NP_001127951.1	Q7L1W4
	LRRC8D	NM_018103.5		c.1003T>C	p.Phe335Leu	missense	Exon 3 of 3	NP_060573.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8D	ENST00000337338.9	TSL:2 MANE Select	c.1003T>C	p.Phe335Leu	missense	Exon 3 of 3	ENSP00000338887.5	Q7L1W4
	LRRC8D	ENST00000394593.7	TSL:1	c.1003T>C	p.Phe335Leu	missense	Exon 3 of 3	ENSP00000378093.3	Q7L1W4
	LRRC8D	ENST00000906496.1		c.1003T>C	p.Phe335Leu	missense	Exon 3 of 3	ENSP00000576555.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.30	B
Vest4		0.73
MutPred		0.36		Loss of catalytic residue at F335 (P = 0.0658)
MVP		0.34
MPC		1.7
ClinPred		0.85	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.72
Mutation Taster		=33/67	disease causing

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

hg19: chr1-90399630;