11-6626391-T-C

Variant names:

• chr11-6626391-T-C
• rs11827437
• NM_003737.4:c.6365-11A>G

Variant summary

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

The ENST00000299441.5(DCHS1):​c.6365-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,610,880 control chromosomes in the GnomAD database, including 108,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9344 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99496 hom.)
• Consequence: DCHS1 ENST00000299441.5 intron
• Scores: Splicing: ADA: 0.00001206
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.48
• Publications: 13 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), PanelApp Australia
• familial mitral valve prolapse

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• van Maldergem syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-6626391-T-C is Benign according to our data. Variant chr11-6626391-T-C is described in ClinVar as Benign. ClinVar VariationId is 259141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000299441.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	NM_003737.4	MANE Select	c.6365-11A>G		intron	N/A	NP_003728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	ENST00000299441.5	TSL:1 MANE Select	c.6365-11A>G		intron	N/A	ENSP00000299441.3

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52445 AN: 151872 Hom.: 9338 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.361

GnomAD2 exomes AF: 0.365 AC: 89668 AN: 245786 AF XY: 0.364

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.442

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.382

GnomAD4 exome AF: 0.368 AC: 537159 AN: 1458888 Hom.: 99496 Cov.: 45 AF XY: 0.367 AC XY: 266506 AN XY: 725504

African (AFR) AF: 0.266 AC: 8888 AN: 33456

American (AMR) AF: 0.348 AC: 15423 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10377 AN: 26086

East Asian (EAS) AF: 0.460 AC: 18200 AN: 39606

South Asian (SAS) AF: 0.307 AC: 26408 AN: 85990

European-Finnish (FIN) AF: 0.391 AC: 20716 AN: 52974

Middle Eastern (MID) AF: 0.393 AC: 2267 AN: 5766

European-Non Finnish (NFE) AF: 0.372 AC: 412935 AN: 1110466

Other (OTH) AF: 0.364 AC: 21945 AN: 60282

GnomAD4 genome AF: 0.345 AC: 52471 AN: 151992 Hom.: 9344 Cov.: 32 AF XY: 0.345 AC XY: 25662 AN XY: 74296

African (AFR) AF: 0.267 AC: 11073 AN: 41446

American (AMR) AF: 0.362 AC: 5539 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1409 AN: 3464

East Asian (EAS) AF: 0.446 AC: 2301 AN: 5154

South Asian (SAS) AF: 0.323 AC: 1553 AN: 4814

European-Finnish (FIN) AF: 0.388 AC: 4097 AN: 10570

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25359 AN: 67944

Other (OTH) AF: 0.358 AC: 757 AN: 2112

Alfa AF: 0.355 Hom.: 3229

Bravo AF: 0.338

Asia WGS AF: 0.348 AC: 1216 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.93
CADD	Benign	0.51
DANN	Benign	0.55
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0080
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: rs11827437; hg19: chr11-6647622; COSMIC: COSV55037249; COSMIC: COSV55037249;