rs750629350

Variant names:

• chr6-130858194-G-A
• rs750629350
• NM_001431.4:c.2960C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-130858194-G-A
• chr6-130858194-G-C

Variant summary

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

The NM_001431.4(EPB41L2):​c.2960C>T​(p.Ser987Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EPB41L2 NM_001431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2960C>T	p.Ser987Leu	missense	Exon 19 of 20	NP_001422.1	O43491-1
	EPB41L2	NM_001350299.2		c.3116C>T	p.Ser1039Leu	missense	Exon 21 of 22	NP_001337228.1	A0A994J5B1
	EPB41L2	NM_001350301.2		c.3017C>T	p.Ser1006Leu	missense	Exon 20 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.2960C>T	p.Ser987Leu	missense	Exon 19 of 20	ENSP00000338481.3	O43491-1
	EPB41L2	ENST00000528282.5	TSL:1	c.2186C>T	p.Ser729Leu	missense	Exon 16 of 17	ENSP00000434308.1	O43491-3
	EPB41L2	ENST00000392427.7	TSL:1	c.1964C>T	p.Ser655Leu	missense	Exon 14 of 15	ENSP00000376222.3	O43491-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251364 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53350

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.52
Sift	Benign	0.27	T
Sift4G	Benign	0.089	T
Polyphen		0.89	P
Vest4		0.69
MutPred		0.51		Gain of sheet (P = 0.0221)
MVP		0.47
MPC		0.14
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.23
gMVP		0.58
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs750629350; hg19: chr6-131179334; COSMIC: COSV61355805; COSMIC: COSV61355805;