16-2029730-C-T

Variant names:

• chr16-2029730-C-T
• rs774643224
• NM_001130012.3:c.362C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001130012.3(NHERF2):​c.362C>T​(p.Pro121Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000482 in 1,555,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: NHERF2 NM_001130012.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.237
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047962576).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130012.3. 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
	NHERF2	NM_001130012.3	MANE Select	c.362C>T	p.Pro121Leu	missense	Exon 2 of 7	NP_001123484.1	Q15599-1
	NHERF2	NM_004785.6		c.362C>T	p.Pro121Leu	missense	Exon 2 of 7	NP_004776.3	Q15599-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHERF2	ENST00000424542.7	TSL:1 MANE Select	c.362C>T	p.Pro121Leu	missense	Exon 2 of 7	ENSP00000408005.2	Q15599-1
	NHERF2	ENST00000432365.6	TSL:1	c.362C>T	p.Pro121Leu	missense	Exon 2 of 7	ENSP00000402857.2	Q15599-2
	NHERF2	ENST00000901526.1		c.362C>T	p.Pro121Leu	missense	Exon 2 of 7	ENSP00000571585.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.000137 AC: 22 AN: 160298 AF XY: 0.000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000157

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.0000285 AC: 40 AN: 1403158 Hom.: 0 Cov.: 48 AF XY: 0.0000332 AC XY: 23 AN XY: 692624

African (AFR) AF: 0.0000314 AC: 1 AN: 31838

American (AMR) AF: 0.000385 AC: 14 AN: 36390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36122

South Asian (SAS) AF: 0.000138 AC: 11 AN: 79448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1081922

Other (OTH) AF: 0.00 AC: 0 AN: 58194

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.00216 AC: 33 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000563 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000362 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.078
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.24
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.022
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.024	D
Polyphen		0.55	P
Vest4		0.15
MutPred		0.24		Loss of methylation at K122 (P = 0.0442)
MVP		0.89
MPC		0.050
ClinPred		0.074	T
GERP RS		2.4
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.30
Mutation Taster		=86/14	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: rs774643224; hg19: chr16-2079731;