Genetic Variant NM_001024611.3:c.2545G>A (chr4-51994477-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001024611.3(LRRC66):c.2545G>A(p.Val849Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LRRC66
NM_001024611.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.115

Publications

0 publications found

Variant links:

Genes affected

LRRC66 (HGNC:34299): (leucine rich repeat containing 66) This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. [provided by RefSeq, Apr 2017]

LRRC66 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04673621).

BP6

Variant 4-51994477-C-T is Benign according to our data. Variant chr4-51994477-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2560214.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024611.3. 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
	LRRC66	NM_001024611.3	MANE Select	c.2545G>A	p.Val849Met	missense	Exon 5 of 5	NP_001019782.1	Q68CR7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC66	ENST00000682860.1	MANE Select	c.2545G>A	p.Val849Met	missense	Exon 5 of 5	ENSP00000508002.1	Q68CR7
LRRC66	ENST00000343457.3	TSL:1	c.2545G>A	p.Val849Met	missense	Exon 4 of 4	ENSP00000341944.3	Q68CR7
LRRC66	ENST00000893847.1		c.2545G>A	p.Val849Met	missense	Exon 5 of 5	ENSP00000563906.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000096912), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.0

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0058

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.50

M_CAP

Benign

0.0087

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

PhyloP100

0.12

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.89

REVEL

Benign

0.019

Sift

Benign

0.13

Sift4G

Benign

0.19

Polyphen

0.056

Vest4

0.038

MutPred

0.19

Gain of disorder (P = 0.0887)

MVP

0.16

MPC

0.031

ClinPred

0.038

GERP RS

-0.56

Varity_R

0.031

gMVP

0.018

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over