rs2277269

Variant names:

• chr11-540719-G-A
• rs2277269
• NM_198075.4:c.35G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-540719-G-A
• chr11-540719-G-C

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.35G>A​(p.Arg12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,612,636 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R12W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (85 hom.)
• Consequence: LRRC56 NM_198075.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.174
• Publications: 6 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=0.002892375).
• BP6: Variant 11-540719-G-A is Benign according to our data. Variant chr11-540719-G-A is described in ClinVar as Benign. ClinVar VariationId is 1598826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00548 (835/152302) while in subpopulation EAS AF = 0.021 (109/5180). AF 95% confidence interval is 0.0178. There are 9 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.35G>A	p.Arg12Gln	missense	Exon 4 of 14	NP_932341.1	Q8IYG6
	LRRC56	NM_001441283.1		c.35G>A	p.Arg12Gln	missense	Exon 4 of 14	NP_001428212.1
	LRRC56	NM_001441284.1		c.35G>A	p.Arg12Gln	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.35G>A	p.Arg12Gln	missense	Exon 4 of 14	ENSP00000270115.7	Q8IYG6
	LRRC56	ENST00000886180.1		c.35G>A	p.Arg12Gln	missense	Exon 4 of 14	ENSP00000556239.1
	LRRC56	ENST00000886182.1		c.35G>A	p.Arg12Gln	missense	Exon 4 of 14	ENSP00000556241.1

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 836 AN: 152184 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.0104 AC: 2577 AN: 247974 AF XY: 0.00884

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.00351

Gnomad EAS exome AF: 0.0195

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00343 AC: 5015 AN: 1460334 Hom.: 85 Cov.: 32 AF XY: 0.00330 AC XY: 2396 AN XY: 726406

African (AFR) AF: 0.00105 AC: 35 AN: 33468

American (AMR) AF: 0.0358 AC: 1600 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 92 AN: 26096

East Asian (EAS) AF: 0.0244 AC: 970 AN: 39680

South Asian (SAS) AF: 0.00178 AC: 153 AN: 86156

European-Finnish (FIN) AF: 0.0303 AC: 1585 AN: 52350

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.000335 AC: 372 AN: 1111828

Other (OTH) AF: 0.00336 AC: 203 AN: 60350

GnomAD4 genome AF: 0.00548 AC: 835 AN: 152302 Hom.: 9 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74446

African (AFR) AF: 0.00130 AC: 54 AN: 41560

American (AMR) AF: 0.0156 AC: 239 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5180

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0317 AC: 337 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00317 Hom.: 13

Bravo AF: 0.00512

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00867 AC: 1052

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ciliary dyskinesia, primary, 39 (1)
-	-	1	LRRC56-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.17
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.028
Sift	Benign	0.097	T
Sift4G	Uncertain	0.057	T
Polyphen		0.44	B
Vest4		0.14
ClinPred		0.017	T
GERP RS		3.0
Varity_R		0.055
gMVP		0.49
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2277269; hg19: chr11-540719;