rs10512747

Variant names:

• chr5-40841639-C-T
• rs10512747
• NM_032587.4:c.257C>T

Variant summary

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

The NM_032587.4(CARD6):​c.257C>T​(p.Ser86Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,284 control chromosomes in the GnomAD database, including 10,399 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.082 (696 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9703 hom.)
• Consequence: CARD6 NM_032587.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.548
• Publications: 27 publications found

Genes affected

CARD6 (HGNC:16394): (caspase recruitment domain family member 6) This gene encodes a protein that contains a caspase recruitment domain (CARD), an antiparallel six-helical bundle that mediates homotypic protein-protein interactions. The encoded protein is a microtubule-associated protein that has been shown to interact with receptor-interacting protein kinases and positively modulate signal transduction pathways converging on activation of the inducible transcription factor NF-kB. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015994012).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD6	NM_032587.4	c.257C>T	p.Ser86Leu	missense_variant	Exon 1 of 3	ENST00000254691.10	NP_115976.2
CARD6	XM_017009989.2	c.257C>T	p.Ser86Leu	missense_variant	Exon 1 of 2		XP_016865478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD6	ENST00000254691.10	c.257C>T	p.Ser86Leu	missense_variant	Exon 1 of 3	1	NM_032587.4	ENSP00000254691.5
CARD6	ENST00000381677.4	c.257C>T	p.Ser86Leu	missense_variant	Exon 1 of 3	1		ENSP00000371093.3

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12513 AN: 152040 Hom.: 696 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0828

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.0576

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0907

GnomAD2 exomes AF: 0.0905 AC: 22513 AN: 248684 AF XY: 0.0942

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.00240

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.110 AC: 160815 AN: 1461126 Hom.: 9703 Cov.: 32 AF XY: 0.109 AC XY: 79562 AN XY: 726860

African (AFR) AF: 0.0166 AC: 554 AN: 33436

American (AMR) AF: 0.0597 AC: 2668 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2758 AN: 26112

East Asian (EAS) AF: 0.00139 AC: 55 AN: 39676

South Asian (SAS) AF: 0.0662 AC: 5704 AN: 86206

European-Finnish (FIN) AF: 0.107 AC: 5727 AN: 53416

Middle Eastern (MID) AF: 0.0863 AC: 497 AN: 5762

European-Non Finnish (NFE) AF: 0.123 AC: 136593 AN: 1111502

Other (OTH) AF: 0.104 AC: 6259 AN: 60362

GnomAD4 genome AF: 0.0822 AC: 12510 AN: 152158 Hom.: 696 Cov.: 33 AF XY: 0.0800 AC XY: 5952 AN XY: 74356

African (AFR) AF: 0.0218 AC: 904 AN: 41530

American (AMR) AF: 0.0826 AC: 1263 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 409 AN: 3472

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5178

South Asian (SAS) AF: 0.0568 AC: 274 AN: 4826

European-Finnish (FIN) AF: 0.106 AC: 1123 AN: 10556

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8263 AN: 67988

Other (OTH) AF: 0.0898 AC: 190 AN: 2116

Alfa AF: 0.108 Hom.: 3418

Bravo AF: 0.0765

TwinsUK AF: 0.117 AC: 434

ALSPAC AF: 0.128 AC: 495

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.120 AC: 1036

ExAC AF: 0.0910 AC: 11047

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		0.55
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.091
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.26
MPC		0.18
ClinPred		0.030	T
GERP RS		4.0
PromoterAI		-0.15	Neutral
Varity_R		0.33
gMVP		0.17
Mutation Taster		=92/8	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: rs10512747; hg19: chr5-40841741;