NM_001005498.4:c.2064+216T>C

Variant names:

• chr17-76472470-A-G
• rs12942767
• NM_001005498.4:c.2064+216T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005498.4(RHBDF2):​c.2064+216T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.937 in 657,042 control chromosomes in the GnomAD database, including 290,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61140 hom., cov: 33)
  • Exomes 𝑓: 0.95 (229784 hom.)
• Consequence: RHBDF2 NM_001005498.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.541
• Publications: 9 publications found

Genes affected

RHBDF2 (HGNC:20788): (rhomboid 5 homolog 2) Predicted to enable protein transporter activity. Predicted to be involved in negative regulation of protein secretion and regulation of epidermal growth factor receptor signaling pathway. Located in plasma membrane. Implicated in palmoplantar keratoderma-esophageal carcinoma syndrome. [provided by Alliance of Genome Resources, Apr 2022]

RHBDF2 Gene-Disease associations (from GenCC):

• palmoplantar keratoderma-esophageal carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-76472470-A-G is Benign according to our data. Variant chr17-76472470-A-G is described in ClinVar as [Benign]. Clinvar id is 1273628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDF2	NM_001005498.4	c.2064+216T>C		intron_variant	Intron 18 of 18	ENST00000675367.1	NP_001005498.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDF2	ENST00000675367.1	c.2064+216T>C		intron_variant	Intron 18 of 18		NM_001005498.4	ENSP00000501790.1

Frequencies

GnomAD3 genomes AF: 0.886 AC: 134757 AN: 152106 Hom.: 61115 Cov.: 33

Gnomad AFR AF: 0.675

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.908

Gnomad ASJ AF: 0.955

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.984

Gnomad OTH AF: 0.898

GnomAD4 exome AF: 0.952 AC: 480486 AN: 504818 Hom.: 229784 AF XY: 0.950 AC XY: 253795 AN XY: 267140

African (AFR) AF: 0.681 AC: 10120 AN: 14858

American (AMR) AF: 0.914 AC: 27034 AN: 29586

Ashkenazi Jewish (ASJ) AF: 0.952 AC: 15283 AN: 16048

East Asian (EAS) AF: 0.895 AC: 27872 AN: 31130

South Asian (SAS) AF: 0.881 AC: 46588 AN: 52858

European-Finnish (FIN) AF: 0.995 AC: 30384 AN: 30546

Middle Eastern (MID) AF: 0.948 AC: 3627 AN: 3824

European-Non Finnish (NFE) AF: 0.984 AC: 292907 AN: 297690

Other (OTH) AF: 0.943 AC: 26671 AN: 28278

GnomAD4 genome AF: 0.886 AC: 134834 AN: 152224 Hom.: 61140 Cov.: 33 AF XY: 0.888 AC XY: 66059 AN XY: 74426

African (AFR) AF: 0.675 AC: 28013 AN: 41514

American (AMR) AF: 0.908 AC: 13888 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 3315 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4844 AN: 5166

South Asian (SAS) AF: 0.875 AC: 4214 AN: 4818

European-Finnish (FIN) AF: 0.996 AC: 10569 AN: 10616

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.984 AC: 66910 AN: 68020

Other (OTH) AF: 0.897 AC: 1895 AN: 2112

Alfa AF: 0.924 Hom.: 21505

Bravo AF: 0.872

Asia WGS AF: 0.899 AC: 3127 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.79
DANN	Benign	0.60
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12942767; hg19: chr17-74468552;