Genetic Variant NHERF2:c.415-1030C>T (chr16-2035294-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001130012.3(NHERF2):c.415-1030C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0683 in 619,598 control chromosomes in the GnomAD database, including 1,959 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.096 ( 1010 hom., cov: 32)

Exomes 𝑓: 0.059 ( 949 hom. )

Consequence

NHERF2
NM_001130012.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.91

Publications

12 publications found

Variant links:

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]

NHERF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NHERF2	NM_001130012.3	MANE Select	c.415-1030C>T	intron	N/A	NP_001123484.1	Q15599-1
NHERF2	NM_004785.6		c.415-1030C>T	intron	N/A	NP_004776.3	Q15599-2
NHERF2	NM_001252073.2		c.82-1030C>T	intron	N/A	NP_001239002.1	Q15599-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NHERF2	ENST00000424542.7	TSL:1 MANE Select	c.415-1030C>T	intron	N/A	ENSP00000408005.2	Q15599-1
NHERF2	ENST00000432365.6	TSL:1	c.415-1030C>T	intron	N/A	ENSP00000402857.2	Q15599-2
NHERF2	ENST00000901526.1		c.415-1030C>T	intron	N/A	ENSP00000571585.1

Frequencies

GnomAD3 genomes

AF:

0.0957

AC:

14529

AN:

151894

Hom.:

998

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.0692

Gnomad AMR

AF:

0.0583

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0664

Gnomad OTH

AF:

0.0795

GnomAD4 exome

AF:

0.0594

AC:

27761

AN:

467586

Hom.:

949

AF XY:

0.0588

AC XY:

12911

AN XY:

219416

show subpopulations

African (AFR)

AF:

0.176

AC:

1414

AN:

8040

American (AMR)

AF:

0.0484

AC:

AN:

578

Ashkenazi Jewish (ASJ)

AF:

0.0329

AC:

AN:

2860

East Asian (EAS)

AF:

0.00

AC:

AN:

2064

South Asian (SAS)

AF:

0.00832

AC:

AN:

9612

European-Finnish (FIN)

AF:

0.120

AC:

AN:

166

Middle Eastern (MID)

AF:

0.0276

AC:

AN:

978

European-Non Finnish (NFE)

AF:

0.0592

AC:

25326

AN:

427926

Other (OTH)

AF:

0.0503

AC:

772

AN:

15362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1190

2380

3570

4760

5950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1302

2604

3906

5208

6510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0959

AC:

14579

AN:

152012

Hom.:

1010

Cov.:

AF XY:

0.0950

AC XY:

7058

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.184

AC:

7603

AN:

41422

American (AMR)

AF:

0.0583

AC:

891

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

122

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00850

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.111

AC:

1173

AN:

10574

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0664

AC:

4510

AN:

67954

Other (OTH)

AF:

0.0787

AC:

166

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

622

1244

1866

2488

3110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0723

Hom.:

593

Bravo

AF:

0.0963

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.93

(source)

DANN

Benign

0.67

PhyloP100

-2.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over