12-6912771-G-A

Position:

• chr12-6912771-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001135217.2(LRRC23):​c.800G>A​(p.Arg267Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000499 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: LRRC23 NM_001135217.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.335

Genes affected

LRRC23 (HGNC:19138): (leucine rich repeat containing 23) Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036712587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC23	NM_001135217.2	c.800G>A	p.Arg267Gln	missense_variant	7/8	ENST00000443597.7	NP_001128689.1
LRRC23	NM_201650.3	c.800G>A	p.Arg267Gln	missense_variant	7/8		NP_964013.1
LRRC23	NM_006992.4	c.759-1120G>A		intron_variant			NP_008923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC23	ENST00000443597.7	c.800G>A	p.Arg267Gln	missense_variant	7/8	1	NM_001135217.2	ENSP00000390932.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000647

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

May 15, 2024

The c.800G>A (p.R267Q) alteration is located in exon 7 (coding exon 6) of the LRRC23 gene. This alteration results from a G to A substitution at nucleotide position 800, causing the arginine (R) at amino acid position 267 to be replaced by a glutamine (Q). 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	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.96
DANN	Benign	0.95
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.24	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.47	N;N
REVEL	Benign	0.028
Sift	Benign	0.65	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.052	B;B
Vest4		0.087
MutPred		0.41		Loss of ubiquitination at K271 (P = 0.0596);Loss of ubiquitination at K271 (P = 0.0596);
MVP		0.29
MPC		0.16
ClinPred		0.097	T
GERP RS		2.5
Varity_R		0.040
gMVP		0.13

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: chr12-7021935; COSMIC: COSV50397480; COSMIC: COSV50397480;