11-540739-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198075.4(LRRC56):c.55C>T(p.Arg19Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,611,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LRRC56 NM_198075.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.10

Genes affected

LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12881514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC56	NM_198075.4	c.55C>T	p.Arg19Trp	missense_variant	4/14	ENST00000270115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC56	ENST00000270115.8	c.55C>T	p.Arg19Trp	missense_variant	4/14	1	NM_198075.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000203 AC: 5 AN: 246762 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133830

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 SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1458992 Hom.: 0 Cov.: 32 AF XY: 0.00000827 AC XY: 6 AN XY: 725704

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74432

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000534 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.55C>T (p.R19W) alteration is located in exon 4 (coding exon 1) of the LRRC56 gene. This alteration results from a C to T substitution at nucleotide position 55, causing the arginine (R) at amino acid position 19 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

This sequence change replaces arginine with tryptophan at codon 19 of the LRRC56 protein (p.Arg19Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs576330767, ExAC 0.007%). This variant has not been reported in the literature in individuals affected with LRRC56-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.090
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.43		Loss of phosphorylation at S17 (P = 0.0731);
MVP		0.39
ClinPred		0.48	T
GERP RS		4.0
Varity_R		0.17
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs576330767; hg19: chr11-540739;