11-6634101-T-A

Variant names:

• chr11-6634101-T-A
• rs2659869
• NM_003737.4:c.1986+17A>T

Variant summary

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

The NM_003737.4(DCHS1):​c.1986+17A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,597,090 control chromosomes in the GnomAD database, including 114,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11552 hom., cov: 32)
  • Exomes 𝑓: 0.38 (103269 hom.)
• Consequence: DCHS1 NM_003737.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.902
• Publications: 12 publications found

Genes affected

DCHS1 (HGNC:13681): (dachsous cadherin-related 1) This gene is a member of the cadherin superfamily whose members encode calcium-dependent cell-cell adhesion molecules. The encoded protein has a signal peptide, 27 cadherin repeat domains and a unique cytoplasmic region. This particular cadherin family member is expressed in fibroblasts but not in melanocytes or keratinocytes. The cell-cell adhesion of fibroblasts is thought to be necessary for wound healing. [provided by RefSeq, Jul 2008]

DCHS1 Gene-Disease associations (from GenCC):

• mitral valve prolapse, myxomatous 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• van Maldergem syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• van Maldergem syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• familial mitral valve prolapse

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000255410 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-6634101-T-A is Benign according to our data. Variant chr11-6634101-T-A is described in ClinVar as Benign. ClinVar VariationId is 259137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003737.4. 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
	DCHS1	NM_003737.4	MANE Select	c.1986+17A>T		intron	N/A	NP_003728.1	Q96JQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	ENST00000299441.5	TSL:1 MANE Select	c.1986+17A>T		intron	N/A	ENSP00000299441.3	Q96JQ0
	ENSG00000255410	ENST00000526633.1	TSL:3	n.211-831T>A		intron	N/A
	ENSG00000255410	ENST00000656961.1		n.309+2672T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58943 AN: 151922 Hom.: 11534 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.393

GnomAD2 exomes AF: 0.381 AC: 91529 AN: 240188 AF XY: 0.379

Gnomad AFR exome AF: 0.397

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.377 AC: 545182 AN: 1445048 Hom.: 103269 Cov.: 50 AF XY: 0.376 AC XY: 269584 AN XY: 716386

African (AFR) AF: 0.400 AC: 13315 AN: 33270

American (AMR) AF: 0.357 AC: 15677 AN: 43888

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 10179 AN: 24890

East Asian (EAS) AF: 0.461 AC: 18205 AN: 39496

South Asian (SAS) AF: 0.327 AC: 27363 AN: 83722

European-Finnish (FIN) AF: 0.387 AC: 20434 AN: 52806

Middle Eastern (MID) AF: 0.397 AC: 2256 AN: 5684

European-Non Finnish (NFE) AF: 0.377 AC: 415265 AN: 1101686

Other (OTH) AF: 0.377 AC: 22488 AN: 59606

GnomAD4 genome AF: 0.388 AC: 59002 AN: 152042 Hom.: 11552 Cov.: 32 AF XY: 0.386 AC XY: 28714 AN XY: 74312

African (AFR) AF: 0.401 AC: 16621 AN: 41454

American (AMR) AF: 0.381 AC: 5822 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1455 AN: 3470

East Asian (EAS) AF: 0.448 AC: 2315 AN: 5164

South Asian (SAS) AF: 0.341 AC: 1640 AN: 4816

European-Finnish (FIN) AF: 0.384 AC: 4063 AN: 10574

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25833 AN: 67964

Other (OTH) AF: 0.390 AC: 822 AN: 2106

Alfa AF: 0.316 Hom.: 1346

Bravo AF: 0.387

Asia WGS AF: 0.372 AC: 1296 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Van Maldergem syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.1
DANN	Benign	0.59
PhyloP100		-0.90
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: rs2659869; hg19: chr11-6655332; COSMIC: COSV55037231;