16-68230309-C-T

Variant names:

• chr16-68230309-C-T
• rs35355998
• NM_024939.3:c.2071G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024939.3(ESRP2):​c.2071G>A​(p.Ala691Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,190 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A691P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (50 hom.)
• Consequence: ESRP2 NM_024939.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.03

Genes affected

ESRP2 (HGNC:26152): (epithelial splicing regulatory protein 2) ESPR2 is an epithelial cell-type-specific splicing regulator (Warzecha et al., 2009 [PubMed 19285943]).[supplied by OMIM, Aug 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002219677).
• BP6: Variant 16-68230309-C-T is Benign according to our data. Variant chr16-68230309-C-T is described in ClinVar as [Benign]. Clinvar id is 780183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0132 (2011/152318) while in subpopulation AFR AF= 0.0452 (1878/41552). AF 95% confidence interval is 0.0435. There are 42 homozygotes in gnomad4. There are 955 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2011 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRP2	NM_024939.3	c.2071G>A	p.Ala691Thr	missense_variant	Exon 15 of 15	ENST00000473183.7	NP_079215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRP2	ENST00000473183.7	c.2071G>A	p.Ala691Thr	missense_variant	Exon 15 of 15	1	NM_024939.3	ENSP00000418748.2

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2009 AN: 152200 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00343 AC: 862 AN: 251452 Hom.: 13 AF XY: 0.00250 AC XY: 340 AN XY: 135896

Gnomad AFR exome AF: 0.0452

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00160 AC: 2333 AN: 1461872 Hom.: 50 Cov.: 31 AF XY: 0.00145 AC XY: 1055 AN XY: 727246

Gnomad4 AFR exome AF: 0.0504

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.0132 AC: 2011 AN: 152318 Hom.: 42 Cov.: 32 AF XY: 0.0128 AC XY: 955 AN XY: 74486

Gnomad4 AFR AF: 0.0452

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.000749 Hom.: 6

Bravo AF: 0.0155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0444 AC: 195

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00424 AC: 515

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ESRP2-related disorder Benign:1

Feb 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Benign	0.72
DEOGEN2	Benign	0.0097	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.076
Sift	Benign	0.52	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0030	B;B
Vest4		0.050
MVP		0.082
MPC		0.29
ClinPred		0.0098	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35355998; hg19: chr16-68264212;