NM_012156.2:c.1245C>T

Variant names:

• chr20-36190742-C-T
• rs77396561
• NM_012156.2:c.1245C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_012156.2(EPB41L1):​c.1245C>T​(p.Pro415Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,218 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (4 hom.)
• Consequence: EPB41L1 NM_012156.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.190
• Publications: 2 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

LOC124904892 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 20-36190742-C-T is Benign according to our data. Variant chr20-36190742-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 529 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.1245C>T	p.Pro415Pro	synonymous	Exon 11 of 22	NP_036288.2	Q9H4G0-1
	EPB41L1	NM_001433605.1		c.1245C>T	p.Pro415Pro	synonymous	Exon 11 of 23	NP_001420534.1
	EPB41L1	NM_001258329.1		c.1245C>T	p.Pro415Pro	synonymous	Exon 12 of 23	NP_001245258.1	A0A0C4DH22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L1	ENST00000338074.7	TSL:1 MANE Select	c.1245C>T	p.Pro415Pro	synonymous	Exon 11 of 22	ENSP00000337168.2	Q9H4G0-1
	EPB41L1	ENST00000373946.7	TSL:1	c.1245C>T	p.Pro415Pro	synonymous	Exon 12 of 23	ENSP00000363057.4	A0A0C4DH22
	EPB41L1	ENST00000202028.9	TSL:1	c.1059C>T	p.Pro353Pro	synonymous	Exon 11 of 20	ENSP00000202028.5	Q9H4G0-2

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152222 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00931

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00132 AC: 332 AN: 251300 AF XY: 0.00110

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000879 AC: 1285 AN: 1461880 Hom.: 4 Cov.: 32 AF XY: 0.000851 AC XY: 619 AN XY: 727240

African (AFR) AF: 0.0101 AC: 338 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.000508 AC: 565 AN: 1112012

Other (OTH) AF: 0.00238 AC: 144 AN: 60396

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74490

African (AFR) AF: 0.00952 AC: 396 AN: 41586

American (AMR) AF: 0.00392 AC: 60 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00398

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		-0.19
PromoterAI		-0.031	Neutral
Mutation Taster		=99/1	polymorphism

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: rs77396561; hg19: chr20-34778664;