1-89933153-G-A

Variant names:

• chr1-89933153-G-A
• NM_001134479.2:c.85G>A

Variant summary

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

The NM_001134479.2(LRRC8D):​c.85G>A​(p.Asp29Asn) 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: 10.0

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]

ENSG00000271949 (HGNC:):

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 rank	MANE	Protein	UniProt
LRRC8D	NM_001134479.2	c.85G>A	p.Asp29Asn	missense_variant	Exon 3 of 3	ENST00000337338.9	NP_001127951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC8D	ENST00000337338.9	c.85G>A	p.Asp29Asn	missense_variant	Exon 3 of 3	2	NM_001134479.2	ENSP00000338887.5
ENSG00000271949	ENST00000370453.5	n.*211G>A		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000359482.5
ENSG00000271949	ENST00000370453.5	n.*211G>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000359482.5

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

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.85G>A (p.D29N) alteration is located in exon 3 (coding exon 1) of the LRRC8D gene. This alteration results from a G to A substitution at nucleotide position 85, causing the aspartic acid (D) at amino acid position 29 to be replaced by an asparagine (N). 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	0.79
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.030	T;T;T;.;T;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.0	.;M;M;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.2	D;N;N;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.011	.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;.;.
Vest4		0.76, 0.71
MutPred		0.48		Gain of MoRF binding (P = 0.0607);Gain of MoRF binding (P = 0.0607);Gain of MoRF binding (P = 0.0607);Gain of MoRF binding (P = 0.0607);Gain of MoRF binding (P = 0.0607);Gain of MoRF binding (P = 0.0607);Gain of MoRF binding (P = 0.0607);
MVP		0.55
MPC		1.5
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.48
gMVP		0.93

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: chr1-90398712;