6-130869636-T-C

Variant names:

• chr6-130869636-T-C
• rs1451273055
• NM_001431.4:c.2534A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001431.4(EPB41L2):​c.2534A>G​(p.Glu845Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E845V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPB41L2 NM_001431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 0 publications found

Genes affected

EPB41L2 (HGNC:3379): (erythrocyte membrane protein band 4.1 like 2) Predicted to enable PH domain binding activity; cytoskeletal protein binding activity; and structural molecule activity. Involved in positive regulation of protein localization to cell cortex. Located in cell junction; nucleoplasm; and plasma membrane. Colocalizes with COP9 signalosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20932716).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001431.4. 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
	EPB41L2	NM_001431.4	MANE Select	c.2534A>G	p.Glu845Gly	missense	Exon 15 of 20	NP_001422.1	O43491-1
	EPB41L2	NM_001350299.2		c.2690A>G	p.Glu897Gly	missense	Exon 17 of 22	NP_001337228.1	A0A994J5B1
	EPB41L2	NM_001350301.2		c.2690A>G	p.Glu897Gly	missense	Exon 17 of 21	NP_001337230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L2	ENST00000337057.8	TSL:1 MANE Select	c.2534A>G	p.Glu845Gly	missense	Exon 15 of 20	ENSP00000338481.3	O43491-1
	EPB41L2	ENST00000524581.5	TSL:1	c.668A>G	p.Glu223Gly	missense	Exon 4 of 9	ENSP00000437207.1	Q6R5J7
	EPB41L2	ENST00000528282.5	TSL:1	c.1834-2055A>G		intron	N/A	ENSP00000434308.1	O43491-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251456 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.046	D
Polyphen		0.60	P
Vest4		0.43
MutPred		0.26		Loss of stability (P = 0.0801)
MVP		0.39
MPC		0.15
ClinPred		0.55	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.41
Mutation Taster		=52/48	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: rs1451273055; hg19: chr6-131190776;