20-36197979-C-T

Variant names:

• chr20-36197979-C-T
• rs757708154
• NM_012156.2:c.1606C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_012156.2(EPB41L1):​c.1606C>T​(p.Arg536Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: EPB41L1 NM_012156.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.86

Genes affected

EPB41L1 (HGNC:3378): (erythrocyte membrane protein band 4.1 like 1) Erythrocyte membrane protein band 4.1 (EPB41) is a multifunctional protein that mediates interactions between the erythrocyte cytoskeleton and the overlying plasma membrane. The encoded protein binds and stabilizes D2 and D3 dopamine receptors at the neuronal plasma membrane. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 20-36197979-C-T is Benign according to our data. Variant chr20-36197979-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435067.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L1	NM_012156.2	c.1606C>T	p.Arg536Cys	missense_variant	Exon 14 of 22	ENST00000338074.7	NP_036288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41L1	ENST00000338074.7	c.1606C>T	p.Arg536Cys	missense_variant	Exon 14 of 22	1	NM_012156.2	ENSP00000337168.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251010 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135774

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461770 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727186

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1606C>T (p.R536C) alteration is located in exon 14 (coding exon 13) of the EPB41L1 gene. This alteration results from a C to T substitution at nucleotide position 1606, causing the arginine (R) at amino acid position 536 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nov 03, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	.;.;.;.;.;D;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.038	D
MutationAssessor	Benign	0.81	.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;D;D;.;.;D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;.;.;D;D;D
Sift4G	Uncertain	0.014	D;T;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;.;.
Vest4		0.55
MutPred		0.52		.;.;.;Loss of helix (P = 3e-04);.;Loss of helix (P = 3e-04);Loss of helix (P = 3e-04);.;
MVP		0.74
MPC		0.95
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.46
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs757708154; hg19: chr20-34785901;