20-36198013-C-G

Variant names:

• chr20-36198013-C-G
• rs6089016
• NM_012156.2:c.1640C>G

Variant summary

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

The NM_012156.2(EPB41L1):​c.1640C>G​(p.Pro547Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,664 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (61 hom.)
• Consequence: EPB41L1 NM_012156.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.43
• Publications: 10 publications found

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]

EPB41L1 Gene-Disease associations (from GenCC):

• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• intellectual disability, autosomal dominant 11

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.005582273).
• BP6: Variant 20-36198013-C-G is Benign according to our data. Variant chr20-36198013-C-G is described in ClinVar as Benign. ClinVar VariationId is 128997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00698 (10202/1461444) while in subpopulation SAS AF = 0.017 (1464/86254). AF 95% confidence interval is 0.0162. There are 61 homozygotes in GnomAdExome4. There are 5308 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High AC in GnomAd4 at 784 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012156.2. 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
	EPB41L1	NM_012156.2	MANE Select	c.1640C>G	p.Pro547Arg	missense	Exon 14 of 22	NP_036288.2
	EPB41L1	NM_001433605.1		c.1640C>G	p.Pro547Arg	missense	Exon 14 of 23	NP_001420534.1
	EPB41L1	NM_001258329.1		c.1640C>G	p.Pro547Arg	missense	Exon 15 of 23	NP_001245258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L1	ENST00000338074.7	TSL:1 MANE Select	c.1640C>G	p.Pro547Arg	missense	Exon 14 of 22	ENSP00000337168.2
	EPB41L1	ENST00000373946.7	TSL:1	c.1640C>G	p.Pro547Arg	missense	Exon 15 of 23	ENSP00000363057.4
	EPB41L1	ENST00000202028.9	TSL:1	c.1418C>G	p.Pro473Arg	missense	Exon 13 of 20	ENSP00000202028.5

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 784 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00712

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00718 AC: 1785 AN: 248490 AF XY: 0.00805

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00519

Gnomad NFE exome AF: 0.00847

Gnomad OTH exome AF: 0.00576

GnomAD4 exome AF: 0.00698 AC: 10202 AN: 1461444 Hom.: 61 Cov.: 38 AF XY: 0.00730 AC XY: 5308 AN XY: 727020

African (AFR) AF: 0.00114 AC: 38 AN: 33472

American (AMR) AF: 0.00255 AC: 114 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00532 AC: 139 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0170 AC: 1464 AN: 86254

European-Finnish (FIN) AF: 0.00592 AC: 314 AN: 53062

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5762

European-Non Finnish (NFE) AF: 0.00693 AC: 7710 AN: 1111970

Other (OTH) AF: 0.00623 AC: 376 AN: 60376

GnomAD4 genome AF: 0.00515 AC: 784 AN: 152220 Hom.: 1 Cov.: 32 AF XY: 0.00495 AC XY: 368 AN XY: 74410

African (AFR) AF: 0.00140 AC: 58 AN: 41538

American (AMR) AF: 0.00503 AC: 77 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4814

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00712 AC: 484 AN: 68004

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00327 Hom.: 0

Bravo AF: 0.00488

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00804 AC: 976

EpiCase AF: 0.00742

EpiControl AF: 0.00771

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	0.69	N
PhyloP100		7.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.030	D
Polyphen		0.0090	B
Vest4		0.47
MVP		0.58
MPC		0.83
ClinPred		0.030	T
GERP RS		5.2
PromoterAI		-0.0074	Neutral
Varity_R		0.16
gMVP		0.41
Mutation Taster		=85/15	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: rs6089016; hg19: chr20-34785935;