NM_018685.5:c.1852G>C

Variant names:

• chr7-36419462-G-C
• rs1184529372
• NM_018685.5:c.1852G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_018685.5(ANLN):​c.1852G>C​(p.Gly618Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G618C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANLN NM_018685.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• Publications: 1 publications found

Genes affected

ANLN (HGNC:14082): (anillin, actin binding protein) This gene encodes an actin-binding protein that plays a role in cell growth and migration, and in cytokinesis. The encoded protein is thought to regulate actin cytoskeletal dynamics in podocytes, components of the glomerulus. Mutations in this gene are associated with focal segmental glomerulosclerosis 8. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ANLN Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-36419462-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 156222.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29475868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANLN	NM_018685.5	c.1852G>C	p.Gly618Arg	missense_variant	Exon 10 of 24	ENST00000265748.7	NP_061155.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANLN	ENST00000265748.7	c.1852G>C	p.Gly618Arg	missense_variant	Exon 10 of 24	1	NM_018685.5	ENSP00000265748.2
ANLN	ENST00000396068.6	c.1741G>C	p.Gly581Arg	missense_variant	Exon 9 of 23	1		ENSP00000379380.2
ANLN	ENST00000428612.5	c.96-5083G>C		intron_variant	Intron 1 of 8	5		ENSP00000413522.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250348 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461234 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726926

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 618 of the ANLN protein (p.Gly618Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ANLN-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ANLN protein function with a negative predictive value of 80%. 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	0.32
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		4.5
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.014	D;T
Polyphen		0.92	P;P
Vest4		0.29
MutPred		0.22		Loss of catalytic residue at V619 (P = 0.0286);.;
MVP		0.45
MPC		0.63
ClinPred		0.88	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.30
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs1184529372; hg19: chr7-36459071;