16-16169805-G-T

Variant names:

• chr16-16169805-G-T
• rs61340537
• NM_001171.6:c.2836C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(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. 16/21 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 NM_001171.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0540
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• inherited pseudoxanthoma elasticum

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 433293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171.6. 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
	ABCC6	NM_001171.6	MANE Select	c.2836C>A	p.Leu946Ile	missense	Exon 22 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.2803C>A	p.Leu935Ile	missense	Exon 22 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.2668C>A	p.Leu890Ile	missense	Exon 21 of 30	NP_001427239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.2836C>A	p.Leu946Ile	missense	Exon 22 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.2836C>A	p.Leu946Ile	missense	Exon 22 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.2836C>A	p.Leu946Ile	missense	Exon 22 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2289 AN: 152200 Hom.: 26 Cov.: 33

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

GnomAD2 exomes AF: 0.0163 AC: 2928 AN: 179624 AF XY: 0.0170

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 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.: 34 AF XY: 0.0179 AC XY: 12603 AN XY: 702914

African (AFR) AF: 0.00264 AC: 86 AN: 32526

American (AMR) AF: 0.00900 AC: 342 AN: 38012

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 389 AN: 25384

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37348

South Asian (SAS) AF: 0.0219 AC: 1778 AN: 81306

European-Finnish (FIN) AF: 0.0299 AC: 1499 AN: 50112

Middle Eastern (MID) AF: 0.0176 AC: 98 AN: 5576

European-Non Finnish (NFE) AF: 0.0183 AC: 19975 AN: 1091332

Other (OTH) AF: 0.0168 AC: 990 AN: 58868

GnomAD4 genome AF: 0.0150 AC: 2289 AN: 152318 Hom.: 26 Cov.: 33 AF XY: 0.0158 AC XY: 1178 AN XY: 74480

African (AFR) AF: 0.00346 AC: 144 AN: 41582

American (AMR) AF: 0.0122 AC: 186 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0244 AC: 118 AN: 4832

European-Finnish (FIN) AF: 0.0362 AC: 385 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0200 AC: 1363 AN: 68016

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0167 Hom.: 52

Bravo AF: 0.0119

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00460 AC: 20

ESP6500EA AF: 0.0153 AC: 131

ExAC AF: 0.0115 AC: 1360

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Autosomal recessive inherited pseudoxanthoma elasticum (2)
-	-	1	Arterial calcification, generalized, of infancy, 2 (1)
-	-	1	Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 (1)
-	-	1	Pseudoxanthoma elasticum, forme fruste (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.2
DANN	Benign	0.098
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.054
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.12
Sift	Benign	0.37	T
Sift4G	Benign	0.52	T
Polyphen		0.15	B
Vest4		0.031
MPC		0.074
ClinPred		0.0048	T
GERP RS		-1.1
Varity_R		0.084
gMVP		0.14
Mutation Taster		=87/13	polymorphism

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: rs61340537; hg19: chr16-16263662; COSMIC: COSV107223272;