1-89933589-T-G

Position:

• chr1-89933589-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001134479.2(LRRC8D):​c.521T>G​(p.Ile174Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 8.02

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC8D	NM_001134479.2	c.521T>G	p.Ile174Ser	missense_variant	3/3	ENST00000337338.9	NP_001127951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC8D	ENST00000337338.9	c.521T>G	p.Ile174Ser	missense_variant	3/3	2	NM_001134479.2	ENSP00000338887	P1
LRRC8D	ENST00000394593.7	c.521T>G	p.Ile174Ser	missense_variant	3/3	1		ENSP00000378093	P1
LRRC8D	ENST00000441269.2	c.521T>G	p.Ile174Ser	missense_variant	2/2	3		ENSP00000405784
LRRC8D	ENST00000527156.1	c.521T>G	p.Ile174Ser	missense_variant	2/2	2		ENSP00000433422

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

The c.521T>G (p.I174S) alteration is located in exon 3 (coding exon 1) of the LRRC8D gene. This alteration results from a T to G substitution at nucleotide position 521, causing the isoleucine (I) at amino acid position 174 to be replaced by a serine (S). 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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T;T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.3	N;N;D;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.74	P;P;.;.
Vest4		0.72
MutPred		0.50		Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);
MVP		0.25
MPC		1.8
ClinPred		0.95	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-90399148;