chr11-540740-G-A

Variant names:

• chr11-540740-G-A
• rs144525570
• NM_198075.4:c.56G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198075.4(LRRC56):​c.56G>A​(p.Arg19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,612,038 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (17 hom.)
• Consequence: LRRC56 NM_198075.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.92
• Publications: 4 publications found

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]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004208058).
• BP6: Variant 11-540740-G-A is Benign according to our data. Variant chr11-540740-G-A is described in ClinVar as Benign. ClinVar VariationId is 1618879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00365 (556/152224) while in subpopulation AFR AF = 0.00883 (367/41562). AF 95% confidence interval is 0.00809. There are 1 homozygotes in GnomAd4. There are 264 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198075.4. 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
	LRRC56	NM_198075.4	MANE Select	c.56G>A	p.Arg19Gln	missense	Exon 4 of 14	NP_932341.1	Q8IYG6
	LRRC56	NM_001441283.1		c.56G>A	p.Arg19Gln	missense	Exon 4 of 14	NP_001428212.1
	LRRC56	NM_001441284.1		c.56G>A	p.Arg19Gln	missense	Exon 4 of 14	NP_001428213.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC56	ENST00000270115.8	TSL:1 MANE Select	c.56G>A	p.Arg19Gln	missense	Exon 4 of 14	ENSP00000270115.7	Q8IYG6
	LRRC56	ENST00000886180.1		c.56G>A	p.Arg19Gln	missense	Exon 4 of 14	ENSP00000556239.1
	LRRC56	ENST00000886182.1		c.56G>A	p.Arg19Gln	missense	Exon 4 of 14	ENSP00000556241.1

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 556 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00205 AC: 506 AN: 246454 AF XY: 0.00206

Gnomad AFR exome AF: 0.00851

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00157 AC: 2287 AN: 1459814 Hom.: 17 Cov.: 32 AF XY: 0.00161 AC XY: 1167 AN XY: 726092

African (AFR) AF: 0.00968 AC: 324 AN: 33464

American (AMR) AF: 0.00273 AC: 122 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.000729 AC: 19 AN: 26080

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00110 AC: 95 AN: 85984

European-Finnish (FIN) AF: 0.0000958 AC: 5 AN: 52168

Middle Eastern (MID) AF: 0.0210 AC: 120 AN: 5726

European-Non Finnish (NFE) AF: 0.00126 AC: 1403 AN: 1111758

Other (OTH) AF: 0.00328 AC: 198 AN: 60326

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.00355 AC XY: 264 AN XY: 74434

African (AFR) AF: 0.00883 AC: 367 AN: 41562

American (AMR) AF: 0.00373 AC: 57 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 67970

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00252 Hom.: 6

Bravo AF: 0.00393

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00223 AC: 270

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00310

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	LRRC56-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.078
DANN	Benign	0.88
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.52	N
PhyloP100		-2.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.011
Sift	Benign	0.35	T
Sift4G	Benign	0.28	T
Polyphen		0.018	B
Vest4		0.050
MVP		0.13
ClinPred		0.0033	T
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.37
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

dbSNP: rs144525570; hg19: chr11-540740;