rs2659872

Variant names:

• chr11-6630579-A-G
• rs2659872
• NM_003737.4:c.4215T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003737.4(DCHS1):​c.4215T>C​(p.Leu1405Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,536,712 control chromosomes in the GnomAD database, including 149,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21787 hom., cov: 34)
  • Exomes 𝑓: 0.43 (127503 hom.)
• Consequence: DCHS1 NM_003737.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.702
• Publications: 16 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

ENSG00000255410 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-6630579-A-G is Benign according to our data. Variant chr11-6630579-A-G is described in ClinVar as Benign. ClinVar VariationId is 259139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.702 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.741 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.4215T>C	p.Leu1405Leu	synonymous	Exon 10 of 21	NP_003728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	ENST00000299441.5	TSL:1 MANE Select	c.4215T>C	p.Leu1405Leu	synonymous	Exon 10 of 21	ENSP00000299441.3
	ENSG00000255410	ENST00000656961.1		n.76A>G		non_coding_transcript_exon	Exon 1 of 3
	ENSG00000255410	ENST00000526633.1	TSL:3	n.-24A>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78131 AN: 151848 Hom.: 21736 Cov.: 34

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.504

GnomAD2 exomes AF: 0.428 AC: 59479 AN: 138810 AF XY: 0.425

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.442

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.425 AC: 588663 AN: 1384752 Hom.: 127503 Cov.: 62 AF XY: 0.425 AC XY: 290642 AN XY: 684366

African (AFR) AF: 0.758 AC: 23418 AN: 30912

American (AMR) AF: 0.411 AC: 14415 AN: 35112

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 10546 AN: 24800

East Asian (EAS) AF: 0.466 AC: 16795 AN: 36074

South Asian (SAS) AF: 0.426 AC: 33793 AN: 79248

European-Finnish (FIN) AF: 0.406 AC: 13960 AN: 34364

Middle Eastern (MID) AF: 0.448 AC: 2404 AN: 5364

European-Non Finnish (NFE) AF: 0.414 AC: 448055 AN: 1081202

Other (OTH) AF: 0.438 AC: 25277 AN: 57676

GnomAD4 genome AF: 0.515 AC: 78233 AN: 151960 Hom.: 21787 Cov.: 34 AF XY: 0.511 AC XY: 37968 AN XY: 74298

African (AFR) AF: 0.748 AC: 31026 AN: 41494

American (AMR) AF: 0.456 AC: 6967 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1503 AN: 3466

East Asian (EAS) AF: 0.460 AC: 2375 AN: 5164

South Asian (SAS) AF: 0.454 AC: 2190 AN: 4826

European-Finnish (FIN) AF: 0.401 AC: 4241 AN: 10566

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.419 AC: 28427 AN: 67856

Other (OTH) AF: 0.500 AC: 1054 AN: 2108

Alfa AF: 0.459 Hom.: 3132

Bravo AF: 0.528

Asia WGS AF: 0.458 AC: 1586 AN: 3458

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	-0.66
CADD	Benign	15
DANN	Benign	0.72
PhyloP100		0.70
Mutation Taster		=97/3	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: rs2659872; hg19: chr11-6651810; COSMIC: COSV55037220; COSMIC: COSV55037220;