chr16-16169805-G-T

Position:

chr16-16169805-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000205557.12(ABCC6):c.2836C>A(p.Leu946Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,572,782 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 33)

Exomes 𝑓: 0.018 ( 280 hom. )

Consequence

ABCC6
ENST00000205557.12 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0540

Variant links:

Genes affected

ABCC6 (HGNC:57): (ATP binding cassette subfamily C member 6) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008]

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003658533).

BP6

Variant 16-16169805-G-T is Benign according to our data. Variant chr16-16169805-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 433293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16169805-G-T is described in Lovd as [Pathogenic]. Variant chr16-16169805-G-T is described in Lovd as [Likely_benign]. Variant chr16-16169805-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.015 (2289/152318) while in subpopulation SAS AF= 0.0244 (118/4832). AF 95% confidence interval is 0.0208. There are 26 homozygotes in gnomad4. There are 1178 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.2836C>A	p.Leu946Ile	missense_variant	22/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.2494C>A	p.Leu832Ile	missense_variant	22/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.2698C>A		non_coding_transcript_exon_variant	21/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.2836C>A	p.Leu946Ile	missense_variant	22/31	1	NM_001171.6	ENSP00000205557	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.2836C>A	p.Leu946Ile	missense_variant, NMD_transcript_variant	22/32	5		ENSP00000483331
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*45C>A		3_prime_UTR_variant, NMD_transcript_variant	21/29	2		ENSP00000405002		O95255-3

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2289

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0246

Gnomad FIN

AF:

0.0362

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0200

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0163

AC:

2928

AN:

179624

Hom.:

AF XY:

0.0170

AC XY:

1639

AN XY:

96334

show subpopulations

Gnomad AFR exome

AF:

0.00313

Gnomad AMR exome

AF:

0.00905

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0215

Gnomad FIN exome

AF:

0.0307

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.0177

AC:

25158

AN:

1420464

Hom.:

280

Cov.:

AF XY:

0.0179

AC XY:

12603

AN XY:

702914

show subpopulations

Gnomad4 AFR exome

AF:

0.00264

Gnomad4 AMR exome

AF:

0.00900

Gnomad4 ASJ exome

AF:

0.0153

Gnomad4 EAS exome

AF:

0.0000268

Gnomad4 SAS exome

AF:

0.0219

Gnomad4 FIN exome

AF:

0.0299

Gnomad4 NFE exome

AF:

0.0183

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0150

AC:

2289

AN:

152318

Hom.:

Cov.:

AF XY:

0.0158

AC XY:

1178

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00346

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0244

Gnomad4 FIN

AF:

0.0362

Gnomad4 NFE

AF:

0.0200

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0166

Hom.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00460

AC:

ESP6500EA

AF:

0.0153

AC:

131

ExAC

AF:

0.0115

AC:

1360

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ABCC6: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -

Arterial calcification, generalized, of infancy, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Pseudoxanthoma elasticum, forme fruste

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.2

DANN

Benign

0.098

DEOGEN2

Benign

0.12

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.98

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.17

REVEL

Benign

0.12

Sift

Benign

0.37

Sift4G

Benign

0.52

Polyphen

0.15

Vest4

0.031

MPC

0.074

ClinPred

0.0048

GERP RS

-1.1

Varity_R

0.084

gMVP

0.14

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over