16-2027089-G-C

Position:

• chr16-2027089-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000424542.7(NHERF2):​c.84G>C​(p.Glu28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 1,458,946 control chromosomes in the GnomAD database, including 503 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. E28G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.035 (310 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (193 hom.)
• Consequence: NHERF2 ENST00000424542.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.461

Genes affected

NHERF2 (HGNC:11076): (NHERF family PDZ scaffold protein 2) This gene encodes a member of the NHERF family of PDZ scaffolding proteins. These proteins mediate many cellular processes by binding to and regulating the membrane expression and protein-protein interactions of membrane receptors and transport proteins. The encoded protein plays a role in intestinal sodium absorption by regulating the activity of the sodium/hydrogen exchanger 3, and may also regulate the cystic fibrosis transmembrane regulator (CFTR) ion channel. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019837916).
• BP6: Variant 16-2027089-G-C is Benign according to our data. Variant chr16-2027089-G-C is described in ClinVar as [Benign]. Clinvar id is 781180.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHERF2	NM_001130012.3	c.84G>C	p.Glu28Asp	missense_variant	1/7	ENST00000424542.7	NP_001123484.1
NHERF2	NM_004785.6	c.84G>C	p.Glu28Asp	missense_variant	1/7		NP_004776.3
NHERF2	XM_047434923.1	c.84G>C	p.Glu28Asp	missense_variant	1/7		XP_047290879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHERF2	ENST00000424542.7	c.84G>C	p.Glu28Asp	missense_variant	1/7	1	NM_001130012.3	ENSP00000408005	P1
NHERF2	ENST00000432365.6	c.84G>C	p.Glu28Asp	missense_variant	1/7	1		ENSP00000402857
NHERF2	ENST00000567504.5	c.186+1423G>C		intron_variant		3		ENSP00000454361

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5282 AN: 151700 Hom.: 310 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00317 AC: 261 AN: 82330 Hom.: 16 AF XY: 0.00254 AC XY: 119 AN XY: 46858

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00636

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00309 AC: 4034 AN: 1307138 Hom.: 193 Cov.: 31 AF XY: 0.00260 AC XY: 1675 AN XY: 644508

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.0000439

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.00744

GnomAD4 genome AF: 0.0349 AC: 5295 AN: 151808 Hom.: 310 Cov.: 33 AF XY: 0.0335 AC XY: 2482 AN XY: 74196

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0192 Hom.: 25

Bravo AF: 0.0393

ESP6500AA AF: 0.0537 AC: 92

ESP6500EA AF: 0.000240 AC: 1

ExAC AF: 0.00133 AC: 77

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.44	N;N
MutationTaster	Benign	0.000038	P;P
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.17
Sift	Benign	0.18	T;T
Sift4G	Uncertain	0.012	D;T
Polyphen		1.0	D;.
Vest4		0.13
MutPred		0.42		Loss of catalytic residue at E28 (P = 0.1447);Loss of catalytic residue at E28 (P = 0.1447);
MVP		0.73
MPC		0.32
ClinPred		0.021	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.72
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs73496087; hg19: chr16-2077090;