chr15-66719608-T-C

Variant names:

• chr15-66719608-T-C
• rs2119260
• NM_005585.5:c.952+3110T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005585.5(SMAD6):​c.952+3110T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 152,158 control chromosomes in the GnomAD database, including 45,970 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 0.77 (45970 hom., cov: 32)
• Consequence: SMAD6 NM_005585.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.114
• Publications: 5 publications found

Genes affected

SMAD6 (HGNC:6772): (SMAD family member 6) The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

SMAD6 Gene-Disease associations (from GenCC):

• craniosynostosis 7

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• radioulnar synostosis, nonsyndromic, susceptibility to

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• aortic valve disease 2

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital radioulnar synostosis

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.952+3110T>C		intron_variant	Intron 3 of 3	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.2107+2468T>C		intron_variant	Intron 4 of 4
SMAD6	XM_011521561.3	c.169+3110T>C		intron_variant	Intron 3 of 3		XP_011519863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.952+3110T>C		intron_variant	Intron 3 of 3	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.*67+2468T>C		intron_variant	Intron 4 of 4	1		ENSP00000452955.1
SMAD6	ENST00000559931.5	n.*67+2468T>C		intron_variant	Intron 3 of 3	3		ENSP00000453446.1

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117452 AN: 152040 Hom.: 45914 Cov.: 32

Gnomad AFR AF: 0.884

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.780

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.773 AC: 117569 AN: 152158 Hom.: 45970 Cov.: 32 AF XY: 0.776 AC XY: 57743 AN XY: 74368

African (AFR) AF: 0.884 AC: 36700 AN: 41522

American (AMR) AF: 0.803 AC: 12293 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2332 AN: 3472

East Asian (EAS) AF: 0.953 AC: 4919 AN: 5160

South Asian (SAS) AF: 0.752 AC: 3622 AN: 4818

European-Finnish (FIN) AF: 0.732 AC: 7744 AN: 10574

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.698 AC: 47449 AN: 67994

Other (OTH) AF: 0.780 AC: 1646 AN: 2110

Alfa AF: 0.644 Hom.: 1797

Bravo AF: 0.786

Asia WGS AF: 0.846 AC: 2943 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.2
DANN	Benign	0.41
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2119260; hg19: chr15-67011946;