rs1346694

Positions:

• chr10-48180973-T-C
• chr10-48180973-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000374201.8(FRMPD2):​c.2620A>G​(p.Ser874Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (10987 hom., cov: 25)
  • Exomes 𝑓: 0.49 (73896 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRMPD2 ENST00000374201.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.791

Genes affected

FRMPD2 (HGNC:28572): (FERM and PDZ domain containing 2) This gene encodes a peripheral membrane protein and is located in a region of chromosome 10q that contains a segmental duplication. This copy of the gene is full-length and is in the telomeric duplicated region. Two other more centromerically proximal copies of the gene are partial and may represent pseudogenes. This full-length gene appears to function in the establishment and maintenance of cell polarization. The protein is recruited to cell-cell junctions in an E-cadherin-dependent manner, and is selectively localized at the basolateral membrane in polarized epithelial cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.039671E-4).
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMPD2	NM_001018071.4	c.2620A>G	p.Ser874Gly	missense_variant	21/29	ENST00000374201.8	NP_001018081.4
FRMPD2	NM_001318191.1	c.2545A>G	p.Ser849Gly	missense_variant	19/27		NP_001305120.1
FRMPD2	XM_047424652.1	c.2617A>G	p.Ser873Gly	missense_variant	21/22		XP_047280608.1
FRMPD2	XM_047424653.1	c.2527A>G	p.Ser843Gly	missense_variant	19/20		XP_047280609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMPD2	ENST00000374201.8	c.2620A>G	p.Ser874Gly	missense_variant	21/29	1	NM_001018071.4	ENSP00000363317	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 63514 AN: 137824 Hom.: 10984 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.459

GnomAD3 exomes AF: 0.553 AC: 42881 AN: 77600 Hom.: 12145 AF XY: 0.552 AC XY: 20959 AN XY: 37968

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.611

Gnomad EAS exome AF: 0.525

Gnomad SAS exome AF: 0.420

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.606

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.485 AC: 364555 AN: 751400 Hom.: 73896 Cov.: 10 AF XY: 0.488 AC XY: 194050 AN XY: 398042

Gnomad4 AFR exome AF: 0.374

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.400

Gnomad4 FIN exome AF: 0.608

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.484

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.461 AC: 63545 AN: 137938 Hom.: 10987 Cov.: 25 AF XY: 0.462 AC XY: 31019 AN XY: 67114

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.411

Gnomad4 ASJ AF: 0.538

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.566

Gnomad4 NFE AF: 0.512

Gnomad4 OTH AF: 0.454

Alfa AF: 0.543 Hom.: 2513

ExAC AF: 0.512 AC: 3919

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T;T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.57	T;T;T
MetaRNN	Benign	0.00020	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.55	.;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	.;N;N
REVEL	Benign	0.055
Sift	Benign	0.14	.;T;T
Sift4G	Uncertain	0.017	.;D;D
Polyphen		0.0020, 0.0040	.;B;B
Vest4		0.036, 0.017
MPC		0.029
ClinPred		0.0075	T
GERP RS		1.3
Varity_R		0.083
gMVP		0.21

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: rs1346694; hg19: chr10-49389016; COSMIC: COSV59714717; COSMIC: COSV59714717;